Biological characterization of a glatiramer acetate related drug product using mammalian and human cells

ABSTRACT

The present invention provides a process for characterizing a glatiramer acetate related drug substance or drug product comprising the steps of:
     a) obtaining a batch of the glatiramer acetate related drug substance or drug product;   b) contacting mammalian cells with an amount of the glatiramer acetate related drug substance or drug product of step a); and   c) i) determining the level of expression of at least one gene selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6; ii) determining the level of expression of at least one gene selected from the group consisting of BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA, wherein if IL1B, IL10, or MMP9 is the at least one gene selected in part (c)(ii), then selecting at least a second different gene from the group other than IL1B, IL10, or MMP9; iii) determining the level of expression of at least one gene selected from the group consisting of C13ORF31, C14ORF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, LOC100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, and ZCCHC7, and ZCCHC7; iv) determining the level of expression of at least one gene selected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOX03B, HSD11B1, HSPD1P6, LOC387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27, 5OD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7; v) determining the level of expression of at least one gene selected from the group consisting of ADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31, C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, MORA, IL4I1, INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, L0054103, LOC388344, LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMPI, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1; vi) determining the level of expression of at least one gene selected from the group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBX045, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566; vii) determining the level of expression of at least one gene selected from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP56400823, DKFZP686O1327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IFI44, IFNGR1, IGFBP3, IL2RG, IL4I1, IL1ORA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, L0051334, LOC201895, LOC284262, L0051334, LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSUl, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6, SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1; viii) determining the level of expression of at least one gene selected from the group consisting of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B, C1ORF71, C1ORF76, ClORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LOC642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, 5YDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1; ix) determining the level of expression of at least one gene selected from the group consisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP; x) determining the level of expression of at least one gene selected from the group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1; xi) determining the level of expression of at least one gene selected from the group consisting of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068, LOC100862473, Mx1, Oas11, Phf11d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2; xii) determining the level of expression of at least one gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2; xiii) determining the level of expression of at least one gene selected from the group consisting of Ahrr, AI607873, Atp10a, AW011738, Casp44, Cxc13, Gm9706, Ifi202b, Ifit2, Ifitm6, I118, Lcn2, LOC100044068, Ms4a6d, Mx1, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2; xiv) determining the level of expression of at least one gene selected from the group consisting of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3, Fam162a, Gfi1, Gpi1, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm, Tpi1, and Trappc6a; xv) determining the level of expression of at least one gene selected from the group consisting of 1600014C10Rik, 2810474O19Rik, 6720475J19Rik, Adam8, Adar, Agrn, Ahrr, AI607873, Amigo2, Ankfy1, Apobec1, Arf4, Asb2, Ascc3, Atp10a, Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chic1, Cmpk2, Csprs, Cxc13, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emr1, Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772, Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-T10, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspa1b, Ifi202b, Ifi203, Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifit1, Ifit1, Ifit2, Ifit3, Ifitm3, I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lga1s3bp, Lga1s9, LOC100041903, LOC100044068, LOC100503923, LOC100505160, LOC100862473, LOC664787, Lpar6, Ly6cl, Ly6c2, Mb21d1, Mitd1, Mlk1, Mmp8, Mnda, Mnda1, Ms4a4c, Ms4a6d, Mx1, Naa20, Nceh1, Ncoa7, Ngp, Nlrc5, Nmral1, Nqo1, Nt5c3, Oas1a, Oas2, Oas3, Oas11, Oas12, Ogfr, Papd7, Parp10, Parp11, Parp12, Parp14, Phf11d, Pik3ap1, Pla2g7, Plec, Pnpt1, Ppm1k, Pydc4, Pyhin1, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1, Slfn1, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9, St3ga16, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmeml84b, Tnfsf10, Torlaip2, Tor3a, Trafd1, Trim25, Trim30a, Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wnt10a, Xaf1, Xaf1, Zc3hav1, Zcchc2, Zfyve26, Znfx1, and Zufsp; xvi) determining the level of expression of at least one gene selected from the group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2; xvii) determining the level of expression of at least one gene selected from the group consisting of CC12, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL4I1, MSC, NQO1, PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF; xviii) determining the level of expression of at least one gene selected from the group consisting of BCL2, CACNA2D3, C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049, LOC645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1, and TDRD7; xix) determining the level of expression of at least one gene selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57, ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6V0C, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35, C13ORF31, C14ORF43, C15ORF39, C17ORF32, C19ORF58, C1ORF122, C1ORF144, C1ORF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88, CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A, CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1A, CHST11, CIDEC, CKB, CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1, DDB1, DGAT2, DKFZP68601327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489, FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, ID2, IER5, IFI30, IFNGR1, IFNGR2, IGFBP3, MORA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, IL4I1, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, LOC113179, LOC338758, LOC440934, L0054103, LOC644242 LOC648998 LOC650429, LOC650446, LOC651816, LOC653524, LOC653361, LOC653840, LOC653361, LOC653506, LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQO1, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU, PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4, PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSPO3, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6, SLC37A2, SLC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG, ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697; xx) determining the level of expression of at least one gene selected from the group consisting of ABHD14B, ACTN1, ACY1L2, ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE, BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41, C16ORF73, C1ORF121, C1ORF63, C1QBP, C1S, C20ORF103, C20ORF112, C20ORF12, C3ORF14, C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2, CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274, LOC220594, LOC254559, LOC284702, LOC285084, LOC285758, LOC340061, LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456, LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H, MT1M, MTBP, MTHFD1, MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG, SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4, SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1, ST3GAL3, STAR, STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1, TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2, VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92; xxi) determining the level of expression of at least one gene selected from the group consisting of CCL2, CCL5, CXCL10, IL1RN, and MMP9; xxii) determining the level of expression of at least one gene selected from the group consisting of CCL5, CXCL10, and MMP9; xxiii) determining the level of expression of at least one gene selected from the group consisting of IL10 and CCL2; xxiv) determining the level of expression of at least one gene selected from the group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10; xxv) determining the level of expression of at least one gene selected from the group consisting of MMP9, CCL2, CCL5, CXCL1, and IL1B; xxvi) determining the level of expression of at least one gene selected from the group consisting of MMP9, CXCL10, CCL2, and CCL5; xxix) determining the level of expression of at least one gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF; or xxx) determining the level of expression of at least one gene selected from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5,
 
thereby characterizing the glatiramer acetate related drug substance or drug product of step a).

This application claims the benefit of U.S. Provisional Application No.62/162,308, filed May 15, 2015, U.S. Provisional Application No.62/134,245, filed Mar. 17, 2015, U.S. Provisional Application No.62/078,369, filed Nov. 11, 2014, U.S. Provisional Application No.62/047,437, filed Sep. 8, 2014, U.S. Provisional Application No.62/025,953, filed Jul. 17, 2014, U.S. Provisional Application No.62/020,358, filed Jul. 2, 2014, and U.S. Provisional Application No.62/019,857, filed Jul. 1, 2014, the contents of which are herebyincorporated by reference.

Throughout this application various publications are referenced bynumerical identifiers in parentheses. Full citations of these referencescan be found following the Examples. The disclosures of thesepublications in their entireties are hereby incorporated by referenceinto this application in order to more fully describe the state of theart to which this invention pertains.

Multiple sclerosis (MS) is a chronic, debilitating autoimmune disease ofthe central nervous system (CNS) with either relapsing-remitting (RR) orprogressive course leading to neurologic deterioration and disability.At time of initial diagnosis, RRMS is the most common form of thedisease (1) which is characterized by unpredictable acute episodes ofneurological dysfunction (relapses), followed by variable recovery andperiods of clinical stability. The vast majority of RRMS patientseventually develop secondary progressive (SP) disease with or withoutsuperimposed relapses. Around 15% of patients develop a sustaineddeterioration of their neurological function from the beginning; thisform is called primary progressive (PP) MS. Patients who haveexperienced a single clinical event (Clinically Isolated Syndrome or“CIS”) and who show lesion dissemination on subsequent magneticresonance imaging (MRI) scans according to McDonald's criteria, are alsoconsidered as having relapsing MS.(2)

With a prevalence that varies considerably around the world, MS is themost common cause of chronic neurological disability in young adults.(3,4) Anderson et al. estimated that there were about 350,000physician-diagnosed patients with MS in the United States in 1990(approx. 140 per 100,000 population).(5) It is estimated that about 2.5million individuals are affected worldwide.(6) In general, there hasbeen a trend toward an increasing prevalence and incidence of MSworldwide, but the reasons for this trend are not fully understood.(5)

Current therapeutic approaches consist of i) symptomatic treatment ii)treatment of acute relapses with corticosteroids and iii) treatmentaimed to modify the course of the disease. Currently approved therapiestarget the inflammatory processes of the disease. Most of them areconsidered to act as immunomodulators but their mechanisms of actionhave not been completely elucidated. Immunosuppressants or cytotoxicagents are also used in some patients after failure of conventionaltherapies. Several medications have been approved and clinicallyascertained as efficacious for the treatment of RR-MS; includingBETASERON®, AVONEX® and REBIF®, which are derivatives of the cytokineinterferon beta (IFNB), whose mechanism of action in MS is generallyattributed to its immunomodulatory effects, antagonizingpro-inflammatory reactions and inducing suppressor cells.(7) Otherapproved drugs for the treatment of MS include Mitoxantrone andNatalizumab.

Copaxone® (Teva Pharmaceutical Industries Ltd.) is a glatiramer acetatedrug product approved for treatment of patients with relapsing-remittingmultiple sclerosis (RRMS) and clinically isolated syndrome (CIS) (8).Glatiramer acetate drug substance (GA), the active substance ofCopaxone®, is a complex mixture of polypeptides and is the first memberof the glatiramoid class; i.e., a complex mixture of syntheticpolypeptides of varying sizes assembled from four naturally occurringamino acids: L-glutamic acid, L-alanine, L-lysine, and L-tyrosine, in adefined molar ratio (9).

GA elicits anti-inflammatory as well as neuroprotective effects invarious animal models of chronic inflammatory and neurodegenerativediseases (10-14) and has been shown to be safe and effective in reducingrelapses and delaying neurologic disability in MS patients followinglong-term treatment (15).

The mechanisms underlying GA therapeutic activity are not fullyelucidated, but GA activity on immune cells has been well demonstrated.GA appears to act as an altered peptide ligand (APL) of encephalitogenicepitopes within myelin basic protein (MBP) (16) and demonstratescross-reactivity with MBP at the humoral and cellular levels (17-23).The unique antigenic sequences of the GA polypeptide mixture competewith myelin antigens for binding to MHC class II molecules on antigenpresenting cells. (APCs) and presentation to the T cell receptor (TCR),resulting in the induction of anergy or deletion of autoreactiveMBP-reactive T cells and proliferation of GA-reactive T cells. Atinitiation of Copaxone® treatment, GA-reactive CD4+ T-cell lines from MSpatients secrete both pro-inflammatory T helper type 1 (Th1) andanti-inflammatory Th2 cytokines (21, 24), but continued exposure toCopaxone® induces a shift in GA-reactive T cells toward the Th2phenotype (21, 23, 25-28).

Copaxone® also increases the number and suppressive capacity ofCD4+CD25+FOXP3+ regulatory T cells, which are functionally impaired inMS patients (29-31). Furthermore, treatment leads to antigen-nonspecificmodulation of APC function. Copaxone® treatment promotes development ofanti-inflammatory type II monocytes characterized by an increase ininterleukin (IL)-10 and transforming growth factor-beta (TGF-β) anddecreased production of IL-12 and tumor necrosis factor (TNF) (32).

SUMMARY OF THE INVENTION

The present invention provides a process for characterizing a glatirameracetate related drug substance or drug product comprising the steps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting mammalian cells with an amount of the glatiramer    acetate related drug substance or drug product of step a); and-   c) i) determining the level of expression of at least one gene    selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2,    ALMS1, ARPC4, CALMS, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1,    DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1,    PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP,    TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6    (hereinafter Gene Group 1); ii) determining the level of expression    of at least one gene selected from the group consisting of BIRC3,    CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B,    IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1,    CARD15, CCL2, CCL5, CD14, IL10, THBD, and NFKBIA (hereinafter Gene    Group 2), wherein if IL1B, IL10, or MMP9 is the at least one gene    selected in part (c) (ii), then selecting at least a second    different gene from the group other than IL1B, IL10, or MMP9; iii)    determining the level of expression of at least one gene selected    from the group consisting of C13ORF31, C14ORF10, C1ORF51, C1ORF63,    CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, LOC100506233, MCM6,    MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1,    TRGC2, TXNDC11, and ZCCHC7 (hereinafter Gene Group 3); iv)    determining the level of expression of at least one gene selected    from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63,    CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOXO3B, HSD11B1,    HSPD1P6, LOC387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6,    SNX27, SOD2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7    (hereinafter Gene Group 4); v) determining the level of expression    of at least one gene selected from the group consisting of ADAM9,    ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5,    ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31,    C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36,    CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2,    EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, GOS2,    HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL1ORA, IL411,    INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344,    LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL,    MITF, MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA,    NFE2L3, NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR,    PRDM1, PSCDBP, PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68,    SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2,    SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B,    TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1 (hereinafter Gene    Group 5); vi) determining the level of expression of at least one    gene selected from the group consisting of ACTN4, BTBD14A, C14ORF10,    CISH, CLK1, CRLF3, FAM62A, FBXO45, GAPDHS, HDAC4, HIC2, HNRPD,    HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B,    WDFY1, ZNF250, and ZNF566 (hereinafter Gene Group 6); vii)    determining the level of expression of at least one gene selected    from the group consisting of A2M, ABCB1, ABCC3, ABHD2, ACPP,    ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2,    ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9,    ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1,    C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF21, C10ORF95, C13ORF31,    C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9,    CD36, CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2,    CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4,    CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L,    DIXDC1, DOCK4, DOK2, DKFZP56400823, DKFZP68601327, EBI2, EMP1, EMR2,    ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2,    FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY,    GLIPR1, GLIS3, GPC1, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA,    HIVEP1, HMOX1, HSPB7, ICAM1, ID2, ID2B, IFI30, IFI44, IFNGR1,    IGFBP3, IL2RG, IL4I1, IL10RA, IL27RA, IL7R, IL10, INA, IRF7, ITGB5,    ITGB7, KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA,    LOC51334, LOC201895, LOC284262, LOC51334, LOC643424, LOC643834,    LOC643847, LOC644242, LOC645238, LOC650429, LOC650446, LOC652543,    LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3,    MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1,    MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSU1, NGEF, NME7, NPTX1,    NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2,    PAQP5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6,    PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1,    PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4,    PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A,    PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1,    PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1,    RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1,    SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6,    SLC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1,    SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A,    TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8,    TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1    (hereinafter Gene Group 7); viii) determining the level of    expression of at least one gene selected from the group consisting    of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B,    C1ORF71, C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27,    C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L,    CEBPD, CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2,    DUSP2, DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1,    GMDS, GPR18, HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4,    KCTD15, KIAA0146, KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4,    LOC201164, LOC284454, LOC387763, LOC642083, LOC648232, MGC2408,    MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8, PDE4B, PDGFD,    PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1,    PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1, SERPINE2,    SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1,    SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2,    SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9,    TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, and YES1 (hereinafter    Gene Group 8); ix) determining the level of expression of at least    one gene selected from the group consisting of AHRR, CCDC36, CYP1B1,    DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP (hereinafter    Gene Group 9); x) determining the level of expression of at least    one gene selected from the group consisting of ADRB2, COTL1,    LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5, TIMP3, and    TSC22D1 (hereinafter Gene Group 10); xi) determining the level of    expression of at least one gene selected from the group consisting    of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203,    Ifi204, Ifi44, Ifi441, Ifit2, Inpp5 b, LOC100044068, LOC100862473,    Mx1, Oas11, Phf11d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18, and Zcchc2    (hereinafter Gene Group 11); xii) determining the level of    expression of at least one gene selected from the group consisting    of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2,    Siglech, and Tspan2 (hereinafter Gene Group 12); xiii) determining    the level of expression of at least one gene selected from the group    consisting of Ahrr, AI607873, Atp10a, AW011738, Casp44, Cxc13,    Gm9706, Ifi202b, Ifit2, Ifitm6, I118, Lcn2, LOC100044068, Ms4a6d,    Mx1, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp, and Zcchc2    (hereinafter Gene Group 13); xiv) determining the level of    expression of at least one gene selected from the group consisting    of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3, Fam162a, Gfi1, Gpi1, Grhpr,    Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm, Tpi1, and Trappc6a    (hereinafter Gene Group 14); xv) determining the level of expression    of at least one gene selected from the group consisting of    1600014C10Rik, 2810474O19Rik, 6720475J19Rik, Adam8, Adar, Agrn,    Ahrr, AI607873, Amigo2, Ankfy1, Apobec1, Arf4, Asb2, Ascc3, Atp10a,    Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chic1, Cmpk2,    Csprs, Cxc13, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2,    Emr1, Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772, Gm14446,    Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15,    H2-T10, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspa1b, Ifi202b, Ifi203,    Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi441, Ifih1, Ifit1, Ifit2,    Ifit3, Ifitm3, I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lgals3    bp, Lgals9, LOC100041903, LOC100044068, LOC100503923, LOC100505160,    LOC100862473, LOC664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitd1, Mlk1,    Mmp8, Mnda, Mnda1, Ms4a4c, Ms4a6d, Mx1, Naa20, Nceh1, Ncoa7, Ngp,    Nlrc5, Nmral1, Nqo1, Nt5c3, Oas1a, Oas2, Oas3, Oas11, Oas12, Ogfr,    Papd7, Parp10, Parp11, Parp12, Parp14, Phf11d, Pik3ap1, Pla2g7,    Plec, Pnpt1, Ppm1k, Pydc4, Pyhin1, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4,    Samd9l, Scin, Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1, Slfn1, Slfn3,    Slfn4, Slfn5, Slfn8, Slfn9, St3gal6, Tcstv3, Tdrd7, Tiparp, Tmem140,    Tmem184b, Tnfsf10, Torlaip2, Tor3a, Trafd1, Trim25, Trim30a,    Trim30d, Trim34a, Trim34b, Tspo, Uba7, Ubr4, Usp18, Wnt10a, Xaf1,    Xaf1, Zc3hav1, Zcchc2, Zfyve26, Znfx1, and Zufsp (hereinafter Gene    Group 15); xvi) determining the level of expression of at least one    gene selected from the group consisting of Ccdc711, D13ERTD608E,    Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, and Tspan2    (hereinafter Gene Group 16); xvii) determining the level of    expression of at least one gene selected from the group consisting    of CC12, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, IL4I1, MSC, NQO1,    PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF    (hereinafter Gene Group 17); xviii) determining the level of    expression of at least one gene selected from the group consisting    of BCL2, CACNA2D3, C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6,    GATM, HAL, HSPA1A, HSPC049, LOC645919, LRMP, OAF, POU4F2, RASGRP2,    RET, SERPINB2, SERPINB8, SPFH1, and TDRD7 (hereinafter Gene Group    18); xix) determining the level of expression of at least one gene    selected from the group consisting of ABCC1, ABHD12, ABHD5, ACPP,    ACSL1, ADFP, ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3,    ALAS1, ALOX5AP, ANKRD57, ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3,    ARRB2, ARRDC4, ASB2, ATF5, ATG7, ATP6V0B, ATP6V0C, ATP9A, ATP9B,    AXL, AYTL1, BCL2A1, BCL3, BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22,    C10ORF54, C10ORF56, C12ORF35, C13ORF31, C14ORF43, C15ORF39,    C17ORF32, C19ORF58, C1ORF122, C1ORF144, C1ORF162, C1ORF21, C1ORF38,    C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88, CALN1, CARD15, CCL2,    CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A, CD40, CD44, CD83,    CD9, CDCA4, CDK5RAP2, CDKN1A, CHST11, CIDEC, CKB, CLEC5A, CLEC7A,    CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2, CSPG2, CTSB,    CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD, CYLD, CYP1B1,    DDB1, DGAT2, DKFZP68601327, DOC1, DOK2, DUSP6, EBI2, ECGF1, ECOP,    EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3,    EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489,    FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15,    GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA,    HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, ID2, IER5, IFI30, IFNGR1,    IFNGR2, IGFBP3, IL1ORA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA,    IL27RA, IL411, IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4,    KIAA0247, KIAA0999, KIAA1505, KIAA1706, KIAA1913, KITLG, KLF13,    KLF4, KLF6, KLHL18, LACTB, LAT, LHX2, LOC113179, LOC338758,    LOC440934, LOC54103, LOC644242, LOC648998, LOC650429, LOC650446,    LOC651816, LOC653524, LOC653361, LOC653840, LOC653361, LOC653506,    LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL, LPXN, LRG1,    LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP, MCL1, ME1,    METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC, MST150,    MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1,    NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQO1,    NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4,    PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU,    PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4,    PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13,    RAB27B, RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1,    RGS1, RGS2, RIN3, RIT1, RND3, RSNL2, RSPO3, RUNX3, SAMSN1, SAP30,    SASH1, SAT1, SDC4, SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1,    SH3TC1, SLAMF8, SLC15A3, SLC16A3, SLC20A1, SLC23A2, SLC25A14,    SLC25A19, SLC25A20, SLC2A1, SLC2A6, SLC37A2, SLC39A8, SLC43A2,    SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11, SLC7A11, SLIC1, SMOX,    SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1, SSH1, ST3GAL5,    STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP, TMEM138,    TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B, TNFRSF21,    TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3, TRIM16,    TRIM16L, TRPA1, TRPS1, TRPS1, T5HZ3, TTLL4, TXNRD1, UBE2S, UGCG,    ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10,    ZFAND5, ZFP36L1, ZNF366, ZNF516, and ZNF697 (hereinafter Gene Group    19); xx) determining the level of expression of at least one gene    selected from the group consisting of ABHD14B, ACTN1, ACY1L2, ADA,    ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL,    ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2,    BMP8B, BRE, BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41,    C16ORF73, C1ORF121, C1ORF63, C1QBP, C1S, C20ORF103, C20ORF112,    C20ORF12, C3ORF14, C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1,    CACNA2D3, CACYBP, CALCOCO2, CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7,    CERKL, CHST12, CHST5, CITED4, CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1,    COL8A2, CUGBP2, CXORF21, DAB1, DENND4A, DEPDC6, DHRS9, DMRT2, DUT,    EIF4A2, ESD, FLJ12078, FLJ20152, FLJ23861, FLJ36166, FOXP1, GATM,    GGA2, GOLGA1, GOLGA8C, GOLGA8D, GOLGA8E, GOLGA8F, GOLGA8G, GPD1L,    GPR18, HADH, HAL, HDAC9, HGF, HIG2, HISPPD1, HNRPA3, HNRPH3, HOXB3,    HSPA1A, HSPA4L, HSPB1, HSPC049, ID2, ID2B, IDH1, IDH1, IHPK2, IRX3,    ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10, LARS, LGR4, LIMA1, LIX1L,    LOC129285, LOC148203, LOC197322, LOC203274, LOC220594, LOC254559,    LOC284702, LOC285084, LOC285758, LOC340061, LOC340061, LOC388189,    LOC474170, LOC643458, LOC645919, LOC646456, LOC90835 LONRF1, LRMP,    LYST, MACF1, MDH1, METTL7B, METTL8, MICAL1, MLSTD1, MNDA, MRPL24,    MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H, MT1M, MTBP, MTHFD1,    MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11, NOC2L, NPAL3,    OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH, PIGM, PIWIL4,    PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3, PTPLAD2,    RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG,    SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4,    SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1,    ST3GAL3, STAR, STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA,    TLE1, TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B,    UBP1, UHRF2, VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1,    WHDC1L2, ZBTB33, ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92    (hereinafter Gene Group 20); xxi) determining the level of    expression of at least one gene selected from the group consisting    of CCL2, CCL5, CXCL10, IL1RN, and MMP9 (hereinafter Gene Group    21); xxii) determining the level of expression of at least one gene    selected from the group consisting of CCL5, CXCL10, and MMP9    (hereinafter Gene Group 22); xxiii) determining the level of    expression of at least one gene selected from the group consisting    of IL10 and CCL2 (hereinafter Gene Group 23); xxiv) determining the    level of expression of at least one gene selected from the group    consisting of IFNg, TNF, CCL3, CXCL8, and IL-10 (hereinafter Gene    Group 24); xxv) determining the level of expression of at least one    gene selected from the group consisting of MMP9, CCL2, CCL5, CXCL1,    and IL1B (hereinafter Gene Group 25); xxvi) determining the level of    expression of at least one gene selected from the group consisting    of MMP9, CXCL10, CCL2, and CCL5 (hereinafter Gene Group 26); xxix)    determining the level of expression of at least one gene selected    from the group consisting of CCL3, MMP9, CCL22, CCL24, CX3CL1,    CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11,    CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF (hereinafter    Gene Group 29); or xxx) determining the level of expression of at    least one gene selected from the group consisting of CCL3, MMP9,    CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B,    CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26,    MIF, IL16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, and CXCL5    (hereinafter Gene Group 30),    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

The present invention also provides a process for discriminating betweenglatiramer acetate related drug substances or drug products comprisingthe steps of:

-   a) characterizing two or more glatiramer acetate related drug    substances or drug products according to the process of the claimed    invention to obtain characteristics of each of the glatiramer    acetate related drug substances or drug products; and-   b) comparing the characteristics of the glatiramer acetate related    drug substances or drug products obtained in step a), thereby    discriminating between glatiramer acetate related drug substances or    drug products.

The present invention also provides a process for characterizing aglatiramer acetate related drug substance or drug product comprising thesteps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting mammalian cells with an amount of the glatiramer    acetate related drug substance or drug product of step a); and-   c) xxii) determining the protein level expression of at least one    protein selected from the group consisting of RANTES, IP-10, and    MMP-9 (hereinafter Protein Group A); xxiii) determining the protein    level expression of at least one protein selected from the group    consisting of IL10 and MCP-1 (hereinafter Protein Group B); xxiv)    determining the protein level expression of at least one protein    selected from the group consisting of IFNg, TNFa, MIP-1a, IL-8, and    IL-10 (hereinafter Protein Group C); xxv) determining the protein    level expression of at least one protein selected from the group    consisting of MMP-9, MCP-1, RANTES, Gro-a, and IL-1b (hereinafter    Protein Group D); xxvi) determining the protein level expression of    at least one protein selected from the group consisting of MMP-9,    IP-10, MCP-1, and RANTES (hereinafter Protein Group E); xxvii)    determining the protein level expression of at least one protein    selected from the group consisting of MIP-1a, MMP-9, MDC, CCL24,    CX3CL1, MIP-3a, MCP-1, TNF-α, IL-8, MCP-4, RANTES, IL-1b, MCP-2,    IL-10, I-TAC, CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, and    MIF (hereinafter Protein Group F); or xxviii) determining the    protein level 3U expression of at least one protein selected from    the group consisting of MIP-1a, MMP-9, MDC, CCL24, CX3CL1, MIP-3a,    MCP-1, TNF-a, IL-8, MCP-4, RANTES, IL-1b, MCP-2, IL-10, I-TAC,    CXCL13, IP-10, MCP-3, CCL1, CXCL1, INF-g, CCL26, MIF, IL-16, IL-6,    TECK, IL-2, MIP-3b, CXCL2, MIG, and CXCL5 (hereinafter Protein Group    G),    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

The present invention also provides a process for characterizing aglatiramer acetate related drug substance or drug product comprising thesteps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting mammalian cells with an amount of the glatiramer    acetate related drug substance or drug product of step a); and-   c) i) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 1; ii) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 2, wherein if IL1B, IL10, or MMP9 is the at    least one gene selected in part (c)(ii), then selecting at least a    second different gene from the group other than IL1B, IL10, or    MMP9; iii) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 3; iv) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 4; v) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 5; vi) determining the protein    level expression of at least one protein produced by a gene selected    from the group consisting of Gene Group 6; vii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 7; viii)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    8; ix) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 9; x) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 10; xi) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 11; xii) determining the protein    level expression of at least one protein produced by a gene selected    from the group consisting of Gene Group 12; xiii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 13; xiv)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    14; xv) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 15; xvi) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 16; xvii) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 17; xviii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 18; xix)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    19; xx) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 20; xxi) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 21; xxii) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 22; xxiii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 23; xxiv)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    24; xxv) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 25; xxvi) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 26; xxix) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 29; or xxx) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 30,    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Framework of studies conducted in mouse splenocytes and humanTHP-1 monocyte cell line.

FIG. 2: Roadmap for human THP-1 monocyte cell line study.

FIG. 3: Levels of Copaxone® measured over time in cell culture mediumfrom human THP-1 monocyte cell line. Copaxone® concentration in mediumover time remains steady in the range of 44-52 μg/mL over 24 hours.

FIGS. 4A-D: Differentially expressed genes in human THP-1 monocyte cellline (a) Increased expression of IL10 with GA treatment at 6 hours forthe single IL10 probeset on the array (207433_at) (FDR adjustedp<3.1e-9); (b-d) Increased expression of IL1RN with GA treatment at 6hours for multiple probesets (adjusted p values as shown).

FIG. 5: Pathways enriched in experimental systems in mouse splenocytes,human THP-1 monocyte cell line and PBMCs from MS patients among topgenes modulated by Copaxone® at 6 hours (subject to FC and adjusted pvalue filters of 1.5 and 1e-5, respectively). The volcano plot show-log(adjusted p value) for the enrichment plotted versus the fold enrichmentscore from DAVID for each pathway. A selected subset of pathways arelabeled.

FIG. 6: Probeset for cytokine-cytokine receptor interaction pathwaygenes significantly modulated by Copaxone® at 6 hours in human THP-1monocyte cell line (subject to FC and adjusted p value filters of 1.5and 1e-5, respectively). The volcano plot show-log (adjusted p value)for differential pexpression plotted versus the fold change from LIMMAfor each probeset.

FIG. 7: MMP9 is significantly upregulated by Probioglat stimulation inhuman THP-1 monocyte cell line compared to Copaxone® stimulation at 6and 24 hours (FDR adjusted p values for each timepoint are 2.74e-6,0.098, and 0.004 for 6, 12, and 24 hours, respectively).

FIG. 8: CD14 expression in human THP-1 monocyte cell line issignificantly higher with Probioglat stimulation compared to Copaxone®stimulation at 6 hours.

FIG. 9: Focus on the “response to LPS” pathway as differentiallyexpressed by Probioglat versus Copaxone® at 6 hours in human THP-1monocyte cell line.

FIG. 10: Pathway-level analysis depicts enrichment among genesupregulated by Probioglat stimulation compared with Copaxone® at 6 hoursin human THP-1 monocyte cell line (a) Pathways enriched among genesupregulated by Probioglat stimulation compared with GA at 6 hours. Thevolcano plot shows −log (adjusted p value) for the enrichment plottedversus the fold enrichment score from DAVID for each pathway; (b) Focuson response to LPS pathway, differentially expressed by Probioglatversus GA at 6 hours. The volcano plot shows −log (adjusted p value) fordifferential expression plotted versus the fold change from LIMMA foreach probeset. A selected subset of pathways are labeled.

FIG. 11: Each present probeset for ICAM1 is significantly upregulated byProbioglat stimulation compared to Copaxone® stimulation at 6 hours inhuman THP-1 monocyte cell line.

FIG. 12: CISH is downregulated by Probioglat stimulation compared toCopaxone® stimulation at 6 hours in human human THP-1 monocyte cellline.

FIG. 13: Upregulation of IL10 with GA treatment in all three studies inmouse splenocytes, human THP-1 monocyte cell line and PBMCs from MSpatients.

FIG. 14: Overlap of genes significantly modulated by GA between studiesin three model systems in mouse splenocytes, human THP-1 monocyte cellline and PBMCs from MS patients.

FIGS. 15A-B: Higher levels of (a) CD14 and (b) CD40 (bottom) are inducedby a Probioglat generic than by Copaxone® or other generics in humanmonocytes.

FIG. 16: Expression of IL1B in Copaxone® and multiple generics in mousesplenocytes.

FIG. 17: Expression of CD44 in Copaxone and Escadra generic in humanmonocytes.

FIG. 18: IL27 expression in Copaxone® and various generics in mousesplenocytes.

FIG. 19: MMP9 expression induced by Copaxone®, Probioglat, and othergenerics in human monocytes.

FIG. 20: Significant gene expression difference are observed betweenCopaxone® and the purported generics Natco and Escadra in many genes,including several relevant to MS.

FIG. 21: MMP14 expression is significantly elevated by TV-5010 relativeto Copaxone® in mouse splenocytes.

FIG. 22: The expression of PGRMC1 and IL1B shows significantly differentexpression following stimulation with proposed generics from differentmanufacturers in human THP-1 monocytes.

FIG. 23: Pathway-level analysis depicts enrichment among genesupregulated by Copaxone® stimulation compared with mannitol control at 6hours in human THP-1 monocyte cell line.

FIG. 24: IL1RN is significantly upregulated by Copaxone stimulation inhuman THP-1 monocyte cell line compared to mannitol control at 6 hours(FDR adjusted p value<2.8e-10).

FIG. 25a : Higher level of CYP1B1 is induced by Polimunol generic thanby Copaxone® in human THP-1 monocyte cell line at 6 hours (FDR adjustedp values<1.5e-10).

FIG. 25b : Higher level of GPR68 is induced by Polimunol generic than byCopaxone® in human THP-1 monocyte cell line at 6 hours (FDR adjusted pvalues<1.5e-5).

FIG. 26: Lower level of ADRB2 is induced by Polimunol generic than byCopaxone® in human THP-1 monocyte cell line at 6 hours (FDR adjusted pvalue<0.009).

FIGS. 27A-E: Copaxone® treatment in mouse splenocytes upregulated (a-b)anti-inflammatory cytokines and (c-d) markers of regulatory T cells, and(e) downregulated pro-inflammatory cytokines.

FIG. 28: Pathways enriched among probesets modulated by Copaxone®relative to medium in splenocytes from mice immunized with Copaxone®.

FIG. 29: IL18 expression is reduced to a greater extent by Copaxone®than Polimunol, regardless of which substance is utilized for theimmunization in mouse splenocytes.

FIG. 30: Pathways enriched among top probesets upregulated by Polimunolrelative to Copaxone® (in Copaxone®-immunized mice).

FIG. 31: Pathways enriched among top probesets upregulated by Polimunolrelative to Copaxone® (in Polimunol-immunized mice).

FIG. 32a : IL-18 signaling pathway (from Dinarello, Front Immunol, 2013;FIG. 1).

FIG. 32b : Mice definicient for IL-18 are resistant to EAE (from Shi, J.Immuno, 2000; FIG. 1a ).

FIG. 33: Type I interferon signaling pathway (from Trinchieri et al,Journal of Experimental Medicine, 2010; FIG. 1)

FIGS. 34A-C: Anti-inflammatory gene IL1RN is significantly upregulatedby Copaxone in human THP-1 monocyte cell line.

FIG. 35: Pathways enriched among top probesets modulated by Copaxonerelative to mannitol control in human THP-1 monocyte cell line.

FIG. 36: Genes in the cytokine-cytokine receptor interaction pathwaymodulated by Copaxone® relative to mannitol control (each pointrepresents a probeset, labeled with its gene annotation) in human THP-1monocyte cell line.

FIG. 37: CYP1B1 is significantly upregulated by Polimunol relative toCopaxone®.

FIG. 38: Pathways significantly enriched among top probesetsdifferentially expressed between Polimunol and Copaxone®.

FIG. 39: Genes in the cytokine-cytokine receptor interaction pathway,which is significantly enriched among top probesets differentiallyexpressed between Polimunol and Copaxone® (each point represents aprobeset, labeled with its gene annotation).

FIG. 40a : Volcano plot showing probesets driving the enrichment of theresponse to lipopolysaccharide pathway among probesets upregulated byPolimunol relative to Copaxone®. The dashed line indicates significancelevel of adjusted p value<0.05.

FIG. 40b : Volcano plot showing probesets driving the enrichment of theresponse to lipopolysaccharide pathway among probesets upregulated byProbioglat relative to Copaxone® in prior study (FDA-2014-P-0933-0001available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein). The dashed line indicates significance level ofadjusted p value<0.05.

FIG. 41: Expression levels of genes differing between Probioglat and GA(a) MMP9 is significantly upregulated following stimulation byProbioglat compared to GA at 6 and 24 hours (FDR-adjusted p values forthe single MMP9 probeset on the chip, 203936_s_at, are 2.74e-6, 0.098,and 0.004 for the 6, 12, and 24 hour timepoints, respectively); (b) CD14expression is significantly higher with stimulation by Probioglatcompared to GA at 6 hours (the single CD14 probeset on the chip isshown, 201743_at); (c) Both present ICAM1 probesets are significantlyupregulated following stimulation by Probioglat compared to GA at 6hours (A: probeset 202637_s_at; B: probeset 202638_s_at); (d) CISH isdownregulated following stimulation by Probioglat compared to GA at 6hours (both present probesets are shown, A: probeset 223961_s_at; B:probeset 223377_x_at).

FIG. 42: Expression levels of genes differing between Probioglat and GAby qRT-PCR in primary human monocytes. CCL2 (p<0.009), CCL5 (p<0.029),CXCL10 (p<0.020), MMP9 (p<0.009), and IL1RN (p<0.013) are expressed morehighly under Probioglat stimulation relative to GA stimulation.

FIG. 43: Principal Component Analysis (PCA; a multivariate approach)showed that the main effect in the first principal component remaineddue to treatment effects after batch correction (a) First principalcomponent accounts for experimental factor (treatment time 6, 12, 24hours); (b) PCA demonstrates batch effect correction required for scandate (legand as in (c)); (c) After batch correction, PCA shows moreuniform distribution of scan dates.

FIG. 44: Box plots showing maximum and minimum expression values forProbioglat (red lines) and Copaxone (blue lines).

FIGS. 45A-B: Protein levels at 24 hours are consistent with upregulationof pro-inflammatory mRNA markers by Probioglat vesus Copaxone® treatmentat 6h (a) CCL, CXCL10 and MMP-9 protein levels are higher withProbioglat versus Copaxone at 24 hr, consistent with mRNA levelobservations by RT-PCR and microarray in THP-1 cells; (b) CCL2 and IL-10protein levels are higher with Probioglat versus Copaxone at 24 hr,consistent with mRNA level observations by microarray (not tested byRT-PCR in THP-1 cells.

FIG. 46: Number of relapses reported to the Patient Support Program inMexico.

FIGS. 47A_E: Levels of Secreted Protein with Polimunol Versus GATreatment: Levels of IFNg, TNFa, MIP1a (CCL3), IL-8 (CXCL8), and IL-10were higher with Polimunol versus GA treatment.

FIGS. 48A-E: Levels of Secreted Protein with Polimunol Versus GATreatment: Consistent with gene level data, levels of MMP-9, MCP-1(CCL2), RANTES (CCL5), Gro-a (CXCL1), and IL-1b were higher withPolimunol versus GA treatment.

FIGS. 49A-E: Levels of Secreted Protein with Probioglat Versus GATreatment: Levels of IFNg, TNFa, MIP1a (CCL3), IL-8 (CXCL8), and IL-10were higher with Probioglat versus GA treatment.

FIGS. 50A-D: Levels of Secreted Protein with Probioglat Versus GATreatment: Consistent with gene level data, levels of MMP-9, MCP-1(CCL2), RANTES (CCL5), and IP-10 (CXCL10) were higher with Probioglatversus GA treatment.

DETAILED DESCRIPTION OF THE INVENTION Embodiments of the Invention

The present invention provides a process for characterizing a glatirameracetate related drug substance or drug product comprising the steps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting mammalian cells with an amount of the glatiramer    acetate related drug substance or drug product of step a); and-   c) i) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 1; ii) determining    the level of expression of at least one gene selected from the group    consisting of Gene Group 2, wherein if IL1B, IL10, or MMP9 is the at    least one gene selected in part (c)(ii), then selecting at least a    second different gene from the group other than IL1B, IL10, or    MMP9; iii) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 3; iv) determining    the level of expression of at least one gene selected from the group    consisting of Gene Group 4; v) determining the level of expression    of at least one gene selected from the group consisting of Gene    Group 5; vi) determining the level of expression of at least one    gene selected from the group consisting of Gene Group 6; vii)    determining the level of expression of at least one gene selected    from the group consisting of Gene Group 7; viii) determining the    level of expression of at least one gene selected from the group    consisting of Gene Group 8; ix) determining the level of expression    of at least one gene selected from the group consisting of Gene    Group 9; x) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 10; xi) determining    the level of expression of at least one gene selected from the group    consisting of Gene Group 11; xii) determining the level of    expression of at least one gene selected from the group consisting    of Gene Group 12; xiii) determining the level of expression of at    least one gene selected from the group consisting of Gene Group    13; xiv) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 14; xv) determining    the level of expression of at least one gene selected from the group    consisting of Gene Group 15; xvi) determining the level of    expression of at least one gene selected from the group consisting    of Gene Group 16; xvii) determining the level of expression of at    least one gene selected from the group consisting of Gene Group    17; xviii) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 18; xix)    determining the level of expression of at least one gene selected    from the group consisting of Gene Group 19; xx) determining the    level of expression of at least one gene selected from the group    consisting of Gene Group 20; xxi) determining the level of    expression of at least one gene selected from the group consisting    of Gene Group 21; xxii) determining the level of expression of at    least one gene selected from the group consisting of Gene Group    22; xxiii) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 23; xxiv)    determining the level of expression of at least one gene selected    from the group consisting of Gene Group 24; xxv) determining the    level of expression of at least one gene selected from the group    consisting of Gene Group 25; xxvi) determining the level of    expression of at least one gene selected from the group consisting    of Gene Group 26; xxix) determining the level of expression of at    least one gene selected from the group consisting of Gene Group 29;    or xxx) determining the level of expression of at least one gene    selected from the group consisting of Gene Group 30,    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

In some embodiments of the present invention step (c) comprises i)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 1; ii) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 3; or vi) determining the level of expression of at least onegene selected from the group consisting of Gene Group 6.

In some embodiments of the present invention, all genes Gene Group 1,are selected for determining the level of expression.

In some embodiments of the present invention, all genes ABCF2, ABI2,ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU,COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1,PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9,TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6, are selected fordetermining the level of expression.

In some embodiments of the present invention, if the at least one geneselected in part(c)(i) is IL10, the process comprises the step ofselecting at least a second different gene from the group of (c)(i) and(c)(ii) other than IL10.

In some embodiments of the present invention, if the at least one geneselected in part(c) (ii) is CARD15, CCL2, CCL5, CD14, IL10, THBD, orNFKBIA, the process comprises the step of selecting at least a seconddifferent gene from the group of (c)(i) and (c)(ii) other than CARD15,CCL2, CCL5, CD14, IL10, THBD, or NFKBIA.

In one or more embodiments of the present invention, if two or moregenes are selected in step (c), then the second or additional geneselected is different from the other selected gene or genes

In one or more embodiments of the present invention, the level ofexpression is determined for all genes identified in Table 5 or Table 12to be involved in one or more than one pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 5 orTable 12 to be involved in at least one pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 5 orTable 12 to be involved in two or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 5 orTable 12 to be involved in three or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 5 orTable 12 to be involved in four or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 5 orTable 12 to be involved in five or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 5 orTable 12 to be involved in six pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene which is involved in onlyone pathway set forth in Table 5 or Table 12.

In one or more embodiments of the present invention, the level ofexpression is determined for at least two genes identified in Table 5 orTable 12 to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least three genes identified in Table 5or Table 12 to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least four genes identified in Table 5or Table 12 to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least five genes identified in Table 5or Table 12 to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least six genes identified in Table 5 orTable 12 to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for all genes identified in Table 6 to beinvolved in one or more than one pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 6 tobe involved in at least one pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 6 tobe involved in two or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 6 tobe involved in three or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 6 tobe involved in four or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 6 tobe involved in five or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene identified in Table 6 tobe involved in six or more pathways.

In one or more embodiments of the present invention, the level ofexpression is determined for at least one gene which is involved in onlyone pathway set forth in Table 6.

In one or more embodiments of the present invention, the level ofexpression is determined for at least two genes identified in Table 6 tobe involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least three genes identified in Table 6to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least four genes identified in Table 6to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least five genes identified in Table 6to be involved in the same pathway.

In one or more embodiments of the present invention, the level ofexpression is determined for at least six genes identified in Table 6 tobe involved in the same pathway.

In one or more embodiments of the present invention, contacting themammalian cells in step (b) comprises i) administering to a mammal apredetermined amount of glatiramer acetate related drug substance ordrug product of step (a), or ii) incubating the cells with an amount ofthe glatiramer acetate related drug substance or drug product of step(a), or a combination thereof; and wherein step (c) comprises i)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 1, thereby characterizing theglatiramer acetate related drug substance or drug product of step (a).

In one or more embodiments of the present invention, contacting themammalian cells in step (b) comprises i) administering to a mammal apredetermined amount of glatiramer acetate related drug substance ordrug product of step (a), and ii) obtaining cells from the mammal at oneor more predetermined time points; and wherein step (c) comprisesdetermining the level of expression of at least one gene selected fromthe group consisting of Gene Group 1, thereby characterizing theglatiramer acetate related drug substance or drug product of step (a).

In one or more embodiments, the mammal is human and the cells areperipheral mononuclear blood cells.

In one or more embodiments, the predetermined time point is 0, 1, 2, or3 months.

In one or more embodiments, contacting the mammalian cells in step (b)comprises incubating monocytic cell line cells with an amount of theglatiramer acetate related drug substance or drug product of step (a);and wherein step (c) comprises determining the level of expression of atleast one gene selected from the group consisting of Gene Group 1; ii)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 2; iii) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 3; iv) determining the level of expression of at least onegene selected from the group consisting of Gene Group 4; v) determiningthe level of expression of at least one gene selected from the groupconsisting of Gene Group 5; vi) determining the level of expression ofat least one gene selected from the group consisting of Gene Group 6;vii) determining the level of expression of at least one gene selectedfrom the group consisting of Gene Group 7; viii) determining the levelof expression of at least one gene selected from the group consisting ofGene Group 8; ix) determining the level of expression of at least onegene selected from the group consisting of Gene Group 9; x) determiningthe level of expression of at least one gene selected from the groupconsisting of Gene Group 10; xvii) determining the level of expressionof at least one gene selected from the group consisting of Gene Group17; xviii) determining the level of expression of at least one geneselected from the group consisting of Gene Group 18; xix) determiningthe level of expression of at least one gene selected from the groupconsisting of Gene Group 19; xx) determining the level of expression ofat least one gene selected from the group consisting of Gene Group 20;xxi) determining the level of expression of at least one gene selectedfrom the group consisting of Gene Group 21; xxii) determining the levelof expression of at least one gene selected from the group consisting ofGene Group 22; xxiii) determining the level of expression of at leastone gene selected from the group consisting of Gene Group 23; xxiv)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 24; xxv) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 25; xxvi) determining the level of expression of at least onegene selected from the group consisting of Gene Group 26; xxix)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 29; or xxx) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 30, thereby characterizing the glatiramer acetate relateddrug substance or drug product of step (a).

In one or more embodiments, contacting the mammalian cells in step (b)comprises incubating monocytic cell line cells with an amount of theglatiramer acetate related drug substance or drug product of step (a);and wherein step (c) comprises i) determining the level of expression ofat least one gene selected from the group consisting of Gene Group 2;ii) determining the level of expression of at least one gene selectedfrom the group consisting of Gene Group 3; iii) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 4; iv) determining the level of expression of at least onegene selected from the group consisting of Gene Group 5; v) determiningthe level of expression of at least one gene selected from the groupconsisting of Gene Group 6; vi) determining the level of expression ofat least one gene selected from the group consisting of Gene Group 7;or, vii) determining the level of expression of at least one geneselected from the group consisting of Gene Group 8; ix) determining thelevel of expression of at least one gene selected from the groupconsisting of Gene Group 9; x) determining the level of expression of atleast one gene selected from the group consisting of Gene Group 10;xvii) determining the level of expression of at least one gene selectedfrom the group consisting of Gene Group 17; xviii) determining the levelof expression of at least one gene selected from the group consisting ofGene Group 18; xix) determining the level of expression of at least onegene selected from the group consisting of Gene Group 19; xx)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 20; xxi) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 21; xxii) determining the level of expression of at least onegene selected from the group consisting of Gene Group 22; xxiii)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 23; xxiv) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 24; xxv) determining the level of expression of at least onegene selected from the group consisting of Gene Group 25; xxvi)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 26; xxix) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 29; or xxx) determining the level of expression of at leastone gene selected from the group consisting of Gene Group 30, therebycharacterizing the glatiramer acetate related drug substance or drugproduct of step a).

In one or more embodiments of the present invention, the mammalian cellsare THP-1 cells.

In one or more embodiments of the present invention, contacting themammalian cells in step (b) comprises i) immunizing a mammal with apredetermined amount of glatiramer acetate related drug substance ordrug product, ii) preparing a culture of cells from the mammal of stepi) at one or more predetermined time points after immunization, and iii)incubating cells from the culture of cells obtained from the mammal withan amount of the glatiramer acetate related drug substance or drugproduct of step (a); and wherein step (c) comprises i) determining thelevel of expression of at least one gene selected from the groupconsisting of Gene Group 1; xi) determining the level of expression ofat least one gene selected from the group consisting of Gene Group 11;xii) determining the level of expression of at least one gene selectedfrom the group consisting of Gene Group 12; xiii) determining the levelof expression of at least one gene selected from the group consisting ofGene Group 13; xiv) determining the level of expression of at least onegene selected from the group consisting of Gene Group 14; xv)determining the level of expression of at least one gene selected fromthe group consisting of Gene Group 15; or xvi) determining the level ofexpression of at least one gene selected from the group consisting ofGene Group 16, thereby characterizing the glatiramer acetate relateddrug substance or drug product of step (a).

In one or more embodiments of the present invention, the glatirameracetate related drug substance or drug product of step (iii) is the sameglatiramer acetate related drug substance or drug product of step (i).

In one or more embodiments of the present invention, the glatirameracetate related drug substance or drug product of step (iii) is adifferent glatiramer acetate related drug substance or drug product ofstep (i).

In one or more embodiments of the present invention, the incubation isfor about 24 hours, for about 12 hours, or for about 6 hours.

In one or more embodiments of the present invention, the predeterminedtime point after immunization is 3 days.

In one or more embodiments of the present invention, the contacting ofstep (b) is in a cell culture.

In one or more embodiments of the present invention, the culture is aprimary culture.

In one or more embodiments of the present invention, the contacting ofstep (b) is in a mammal.

In one or more embodiments of the present invention, the mammal is arodent or human.

In one or more embodiments of the present invention, the glatirameracetate related drug substance or drug product is other than glatirameracetate drug substance or drug product.

In one or more embodiments of the present invention, the cell is of atype i) selected from the group of cell types consisting of FoxP3+ Tcells, regulatory T cells, natural killer T cells, T helper 2 cells,CD8+ T cells, CD4+ T cells, B cells, macrophage cells, monocyte cells,eosinophils, dendritic cells, granulocytes, megakaryocytes, and myeloidprogenitors; ii) selected from the group of cell types identified inTable 9; iii) selected from the group of cell types identified in Table10; or iv) selected from the group of cell types identified in Table 11.

In one or more embodiments of the present invention, the process ofcharacterizing two or more glatiramer acetate related drug substances ordrug products further comprises obtaining characteristics of each of theglatiramer acetate related drug substances or drug products; andcomparing the characteristics of the drug related substances or drugproducts, thereby discriminating between glatiramer acetate related drugsubstances or drug products.

In one or more embodiments of the present invention, the mammal is arodent or human.

In one or more embodiments of the present invention, the level ofexpression is determined in hematological cells.

In one or more embodiments of the present invention, the level ofexpression is determined in splenocytes.

In one or more embodiments of the present invention, the level ofexpression is determined in monocytes.

In one or more embodiments of the present invention, the monocytes areTHP-1.

In one or more embodiments of the present invention, the level ofexpression is determined in peripheral blood mononuclear cells.

In one or more embodiments of the present invention, the peripheralblood mononuclear cells are from a human.

In one or more embodiments of the present invention, the human haspreviously been treated with a glatiramer acetate related drug substanceor drug product.

In one or more embodiments of the present invention, the human is anaïve human.

In one or more embodiments of the present invention, the human is aglatiramoid naïve human.

In one or more embodiments of the present invention, the human isafflicted with RRMS.

In one or more embodiments of the present invention, the rodent is amouse.

In one or more embodiments of the present invention, the mouse is afemale (SJL X BALB/C) F1 mouse.

In one or more embodiments of the present invention, the mouse is about8 to 12 weeks old.

In one or more embodiments of the present invention, the primary cultureis a culture of spleen cells.

In some embodiments of the present invention, the primary culture is aculture of lymph node cells.

In some embodiments of the present invention, the primary culture ofspleen cells is prepared about 3 days after immunization.

In one or more embodiments of the present invention, the glatirameracetate related drug substance is a glatiramoid or the glatirameracetate related drug product comprises a glatiramoid.

In one or more embodiments of the present invention, the glatirameracetate related drug substance is a glatiramoid other than glatirameracetate related drug substance, or the glatiramer acetate related drugproduct comprises a glatiramoid other than glatiramer acetate drugsubstance.

In one or more embodiments of the present invention, process forcharacterizing a glatiramer acetate related drug substance or drugproduct comprising the steps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting a first group of mammalian cells with an amount of the    glatiramer acetate related drug substance or drug product of step    a);-   c) contacting a second group of mammalian cells of the same type    with an amount of a reference standard; and-   d) determining a set of genes differentially expressed by the first    group after the contacting of step (b) relative to genes expressed    by the second group after the contacting of step (c),    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

In one or more embodiments of the present invention, the cells are THP-1cells.

In one or more embodiments of the present invention, the referencestandard is glatiramer acetate related drug substance or drug product.

In one or more embodiments of the present invention, the referencestandard is mannitol

In one or more embodiments of the present invention, the referencestandard is medium.

In one or more embodiments of the present invention, the determiningstep (d) comprises comparing the expression of genes expressed by thefirst group to the expression of genes expressed by the second group.

In one or more embodiments of the present invention, the determiningstep (d) comprises comparing the expression of genes by bother the firstgroup of cells and by the second group of cells to expression of thegenes by the same type of cells exposed to mannitol or medium.

In one or more embodiments of the present invention, process fordiscriminating between glatiramer acetate related drug substances ordrug products comprising the step of characterizing two or moreglatiramer acetate related drug substances or drug products to obtaincharacteristics of each of the glatiramer acetate related drugsubstances or drug products; and comparing the characteristics of theglatiramer acetate related drug substances or drug products, therebydiscriminating between glatiramer acetate related drug substances ordrug products.

In some embodiments of the present invention in a process for producinga drug product comprising a glatiramer acetate related drug substancewhich involves an array of testing, the improvement comprising includingin the array of testing the steps of:

-   a) characterizing the glatiramer acetate related drug substance    according to the process of any one of the above characterization    methods; and-   b) i) including the batch of the glatiramer acetate related drug    substance in the production of the drug product if the level of    expression of one or more genes selected from the group consisting    of Gene Group 1 is not substantially identical to the level of    expression by the same type of cells in the absence of the    glatiramer acetate related drug substance under the same    conditions; ii) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 2 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; iii)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group 3    is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; iv) including the batch of the    glatiramer acetate related drug substance in the production of the    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 4 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; v) including the batch of the glatiramer acetate related    drug substance in the production of the drug product if the level of    expression of one or more genes selected from the group consisting    of Gene Group 5 is substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; vi)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    6, is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; vii) including the batch of the    glatiramer acetate related drug substance in the production of the    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 7, is upregulated    to the level of expression by the same type of cells in the absence    of the glatiramer acetate related drug substance under the same    conditions; viii) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 8, is downregulated to the level of    expression by the same type of cells in the absence of the    glatiramer acetate related drug substance under the same conditions;    or ix) including the batch of the glatiramer acetate related drug    substance in the production of the drug product if the level of    expression of one or more genes selected from the group consisting    of Gene Group 9 is substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; x)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    10 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xi) including the batch of the    glatiramer acetate related drug substance in the production of the    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 11 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xii) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 12 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xiii)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    13 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xiv) including the batch of the    glatiramer acetate related drug substance in the production of the    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 14 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xv) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 15 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xvi)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    16 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xvii) including the batch of    the glatiramer acetate related drug substance in the production of    the drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 17 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xviii) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 18 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xix)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    19 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xx) including the batch of the    glatiramer acetate related drug substance in the production of the    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 20 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxi) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 21 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxii)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    22 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xxiii) including the batch of    the glatiramer acetate related drug substance in the production of    the drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 23 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxiv) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 24 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxv)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    25 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xxvi) including the batch of    the glatiramer acetate related drug substance in the production of    the drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 26 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxix) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 29 is substantially identical to the level    of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; or xxx)    including the batch of the glatiramer acetate related drug substance    in the production of the drug product if the level of expression of    one or more genes selected from the group consisting of Gene Group    30 is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 1 is notsubstantially identical to the level of expression by the same type ofcells in the absence of the glatiramer acetate related drug substanceunder the same conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of ABCF2, ABI2, ACP6, AFG3L2,ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1,DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1, POLI,REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1,TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 is not substantially identicalto the level of expression by the same type of cells in the absence ofthe glatiramer acetate related drug substance under the same conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 2 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 3 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 4 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 5 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 6 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises i) includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of ABI2, ARPC4, CD84, CLU, HFE,and IL10 is upregulated relative to the level of expression by the sametype of cells in the absence of the glatiramer acetate related drugsubstance under the same conditions; or ii) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of ABCF2, ACP6, AFG3L2, CHAF1A, COX11, LPHN1, NACA,OLAH, POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TSHZ1, TSPAN13,UBAP2, VDAC2, and TSHZ1 is downregulated relative to the level ofexpression by the same type of cells in the absence of the glatirameracetate related drug substance under the same conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises, if, one ormore genes selected from the group consisting of ABI2, ARPC4, HFE, andIL10 is upregulated relative to the level of expression by the same typeof cells in the absence of the glatiramer acetate related drug substanceunder the same conditions, then including the batch of the glatirameracetate related drug substance in the production of the drug product.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises, if, one ormore genes selected from the group consisting of ACP6, LPHN1, POLI,SEC31A, SYNCRIP, and TSHZ1 is downregulated relative to the level ofexpression by the same type of cells in the absence of the glatirameracetate related drug substance under the same conditions, then includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises i) includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of CCL2, CCL5, MMP1, MMP9,CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD, NFKBIA, IL10, PRDM1 issubstantially identical to the level of expression by the same type ofcells in the presence of glatiramer acetate drug substance under thesame conditions; ii) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of CISH and HSPD1 is substantially identical to the level ofexpression by the same type of cells in the presence of glatirameracetate drug substance under the same conditions; iii) including thebatch of the glatiramer acetate related drug substance in the productionof the drug product if the level of expression of one or more genesselected from the group consisting of CC124, CCR1, CSF1R, CX3CR1, IL27,IFNGR1, IL2RG, and IL7R is not substantially identical to the level ofexpression by the same type of cells in the absence of the glatirameracetate drug related substance under the same conditions; iv) includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of PGRMC1 isupregulated or substantially identical to the level of expression by thesame type of cells in the absence of the glatiramer acetate related drugsubstance under the same conditions; v) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of MMP14 is substantially identicalto the level of expression by the same type of cells in the presence ofglatiramer acetate drug substance under the same conditions; vi)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of IL1RNis upregulated to the level of expression by the same type of cells inthe absence of the glatiramer acetate related drug substance under thesame conditions; or vii) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of IL1B is substantially identical to the level ofexpression by the same type of cells in the presence of glatirameracetate drug substance under the same conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 5 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 6 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 7, is upregulatedto the level of expression by the same type of cells in the absence ofthe glatiramer acetate related drug substance under the same conditions.

In one or more embodiments of the present invention, in the process forproducing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product if the level of expression of one or moregenes selected from the group consisting of Gene Group 8, isdownregulated to the level of expression by the same type of cells inthe absence of the glatiramer acetate related drug substance under thesame conditions.

In some embodiments of the present invention in a process for releasinga drug product comprising a glatiramer acetate related drug substance,which process involves an array of testing, the improvement comprisingincluding in the array of testing the steps of:

-   a) characterizing the glatiramer acetate related drug product    according to the process of any one of the above characterization    methods; and-   b) i) releasing the batch of the glatiramer acetate related drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 1 is not substantially    identical to the level of expression by the same type of cells in    the absence of the glatiramer acetate related drug product under the    same conditions; ii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 2 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; iii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 3 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; iv) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 4 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; v) releasing the batch of the glatiramer acetate related    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 5 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; vi) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 6, is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; vii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 7, is upregulated    to the level of expression by the same type of cells in the absence    of the glatiramer acetate related drug substance under the same    conditions; viii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 8, is downregulated    to the level of expression by the same type of cells in the absence    of the glatiramer acetate related drug substance under the same    conditions, ix) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 9 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; x) releasing the batch of the glatiramer acetate related    drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 10 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug product under the same    conditions; xi) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 11 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 12 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xiii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 13 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xiv) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 14 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xv) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 15 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xvi) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 16 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xvii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 17 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xviii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 18 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xix) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 19 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xx) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 20 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxi) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 21 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 22 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxiii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 23 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxiv) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 24 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxv) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 25 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxvi) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 26 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxix) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 29 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; or xxx) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more genes    selected from the group consisting of Gene Group 30 is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 1 is not substantially identical to the level of expressionby the same type of cells in the absence of the glatiramer acetaterelated drug product under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6,CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1,OLAH, PATZ1, PDK1, POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1,SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6is not substantially identical to the level of expression by the sametype of cells in the absence of the glatiramer acetate related drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 2 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 3 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 4 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 5, is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 6 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises i) releasingthe batch of the glatiramer acetate related drug product if the level ofexpression of one of more genes selected from the group consisting ofABI2, ARPC4, CD84, CLU, HFE, and IL10 is upregulated relative to thelevel of expression by the same type of cells in the absence of theglatiramer acetate related drug product under the same conditions; orii) releasing the batch of the glatiramer acetate related drug productif the level of expression of one of more genes selected from the groupconsisting of ABCF2, ACP6, AFG3L2, CHAF1A, COX11, LPHN1, NACA, OLAH,POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TSHZ1, TSPAN13, UBAP2,VDAC2, and TSHZ1 is downregulated relative to the level of expression bythe same type of cells in the absence of the glatiramer acetate relateddrug product under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug substance further comprises, if, one ormore genes selected from the group consisting of ABI2, ARPC4, HFE, andIL10 is upregulated relative to the level of expression by the same typeof cells in the absence of the glatiramer acetate related drug productunder the same conditions, then releasing the batch of the glatirameracetate related drug product.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises, if, one ormore genes selected from the group consisting of ACP6, LPHN1, POLI,SEC31A, SYNCRIP, and TSHZ1 is downregulated relative to the level ofexpression by the same type of cells in the presence of the glatirameracetate drug product under the same conditions, then releasing the batchof the glatiramer acetate related drug product.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises i) releasingthe batch of the glatiramer acetate related drug product if the level ofexpression of one of more genes selected from the group consisting ofCCL2, CCL5, MMP1, MMP9, CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD,NFKBIA, IL10, PRDM1 is substantially identical to the level ofexpression by the same type of cells in the presence of glatirameracetate drug substance under the same conditions; ii) releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one of more genes selected from the group consisting ofCISH and HSPD1 is substantially identical to the level of expression bythe same type of cells in the presence of glatiramer acetate drugsubstance under the same conditions; iii) releasing the batch of theglatiramer acetate related drug product if the level of expression ofone of more genes selected from the group consisting of CC124, CCR1,CSF1R, CX3CR1, IL27, IFNGR1, IL2RG, and IL7R is not substantiallyidentical to the level of expression by the same type of cells in theabsence of the glatiramer acetate drug related substance under the sameconditions; iv) releasing the batch of the glatiramer acetate relateddrug product if the level of expression of PGRMC1 is upregulated orsubstantially identical to the level of expression by the same type ofcells in the absence of the glatiramer acetate related drug substanceunder the same conditions; v) releasing the batch of the glatirameracetate related drug product if the level of expression of MMP14 issubstantially identical to the level of expression by the same type ofcells in the presence of glatiramer acetate drug substance under thesame conditions; vi) releasing the batch of the glatiramer acetaterelated drug product if the level of expression of IL1RN is upregulatedto the level of expression by the same type of cells in the absence ofthe glatiramer acetate related drug substance under the same conditions;or vii) releasing the batch of the glatiramer acetate related drugproduct if the level of expression of IL1B is substantially identical tothe level of expression by the same type of cells in the presence ofglatiramer acetate drug substance under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 5, is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 6 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugproduct under the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 7, is upregulated to the level of expression by the same typeof cells in the absence of the glatiramer acetate related drug substanceunder the same conditions.

In one or more embodiments of the present invention, in the process forreleasing a drug product comprising a glatiramer acetate related drugsubstance which involves an array of testing, the characterizing theglatiramer acetate related drug product further comprises releasing thebatch of the glatiramer acetate related drug product if the level ofexpression of one or more genes selected from the group consisting ofGene Group 8, is downregulated to the level of expression by the sametype of cells in the absence of the glatiramer acetate related drugsubstance under the same conditions.

In one or more embodiments of the present invention, a glatirameracetate related drug product produced by a process of the presentinvention, wherein the glatiramer acetate related drug product is otherthan glatiramer acetate drug product.

In one or more embodiments of the present invention, a glatirameracetate related drug product other than glatiramer acetate drug productwhich is capable of inducing a level of expression of ABCF2, ABI2, ACP6,AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11,DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1, OLAH, PATZ1, PDK1,POLI, REEP5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40,TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6 that is not substantiallyidentical to the level of expression of the genes induced in the sametpe of cells and under the same conditions in the absence of theglatiramer acetate related drug product.

In one or more embodiments of the present invention, a glatirameracetate related drug product, wherein the glatiramer acetate relateddrug product is capable of inducing a level of expression of Gene Group1.

In one or more embodiments of the present invention, the glatirameracetate related drug product, which is capable of upregulating genesABI2, ARPC4, HFE, and IL10 relative to the level of expression of thegenes in the same type of cells and under the same conditions in theabsence of the glatiramer acetate related drug product, and capable ofdownregulating genes ACP6, LPHN1, POLI, SEC31A, SYNCRIP, and TSHZ1relative to the level of expression of the genes in the same type ofcells and under the same conditions in the absence of the glatirameracetate related drug product.

In one or more embodiments of the present invention, a glatirameracetate related drug product other than glatiramer acetate drug productwhich is capable of inducing a level of expression of Gene Group 7 andGene Group 8, that is not substantially identical to the level ofexpression of the genes induced in the same type of cells and under thesame conditions in the absence of the glatiramer acetate related drugproduct.

In one or more embodiments of the present invention, the glatirameracetate related drug product, which is capable of upregulating genesGene Group 7, relative to the level of expression of the genes in thesame type of cells and under the same conditions in the absence of theglatiramer acetate related drug product, and capable of downregulatinggenes Gene Group 8 relative to the level of expression of the genes inthe same type of cells and under the same conditions in the absence ofthe glatiramer acetate related drug product

In some embodiments of the present invention, the process furthercomprises i) determining the one or more proteins produced by each ofthe one of more genes selected in step c); and ii) determining proteinlevel expression for each protein in step i).

In some embodiments of the present invention, the process furthercomprises i) determining the one or more proteins produced by each ofthe one of more genes selected in step b); and ii) determining proteinlevel expression for each protein in step i).

In some embodiments of the present invention, the process furthercomprises determining the set of proteins produced by each gene of theset of genes in step d).

In some embodiments of the present invention, in a process forcharacterizing a glatiramer acetate related drug substance or drugproduct comprising the steps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting mammalian cells with an amount of the glatiramer    acetate related drug substance or drug product of step a); and-   c) xxii) determining the protein level expression of at least one    protein selected from the group consisting of Protein Group    A; xxiii) determining the protein level expression of at least one    protein selected from the group consisting of Protein Group B; xxiv)    determining the protein level expression of at least one protein    selected from the group consisting of Protein Group C; xxv)    determining the protein level expression of at least one protein    selected from the group consisting of Protein Group D; xxvi)    determining the protein level expression of at least one protein    selected from the group consisting of Protein Group E; xxvii)    determining the protein level expression of at least one protein    selected from the group consisting of Protein Group F; or xxviii)    determining the protein level expression of at least one protein    selected from the group consisting of Protein Group G,    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

In some embodiments of the present invention, in a process forcharacterizing a glatiramer acetate related drug substance or drugproduct comprising the steps of:

-   a) obtaining a batch of the glatiramer acetate related drug    substance or drug product;-   b) contacting mammalian cells with an amount of the glatiramer    acetate related drug substance or drug product of step a); and-   c) i) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 1; ii) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 2, wherein if IL1B, IL10, or MMP9 is the at    least one gene selected in part (c)(ii), then selecting at least a    second different gene from the group other than IL1B, IL10, or    MMP9; iii) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 3; iv) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 4; v) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 5; vi) determining the protein    level expression of at least one protein produced by a gene selected    from the group consisting of Gene Group 6; vii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 7; viii)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    8; ix) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 9; x) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 10; xi) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 11; xii) determining the protein    level expression of at least one protein produced by a gene selected    from the group consisting of Gene Group 12; x) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 13; xiv)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    14; xv) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 15; xvi) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 16; xvii) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 17; xviii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 18; xix)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    19; xx) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 20; xxi) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 21; xxii) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 22; xxiii) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 23; xxiv)    determining the protein level expression of at least one protein    produced by a gene selected from the group consisting of Gene Group    24; xxv) determining the protein level expression of at least one    protein produced by a gene selected from the group consisting of    Gene Group 25; xxvi) determining the protein level expression of at    least one protein produced by a gene selected from the group    consisting of Gene Group 26; xxix) determining the protein level    expression of at least one protein produced by a gene selected from    the group consisting of Gene Group 29; or xxx) determining the    protein level expression of at least one protein produced by a gene    selected from the group consisting of Gene Group 30,    thereby characterizing the glatiramer acetate related drug substance    or drug product of step a).

In some embodiments of the present invention the process, whereincontacting the mammalian cells in step (b) comprises incubatingmonocytic cell line cells with an amount of the glatiramer acetaterelated drug substance or drug product of step (a); and wherein step (c)comprises xxii) determining the protein level expression of at least oneprotein selected from the group consisting of Protein Group A; xxiii)determining the protein level expression of at least one proteinselected from the group consisting of Protein Group B; xxiv) determiningthe protein level expression of at least one protein selected from thegroup consisting of Protein Group C; xxv) determining the protein levelexpression of at least one protein selected from the group consisting ofProtein Group D; xxvi) determining the protein level expression of atleast one protein selected from the group consisting of Protein Group E;xxvii) determining the protein level expression of at least one proteinselected from the group consisting of Protein Group F; or xxviii)determining the protein level expression of at least one proteinselected from the group consisting of Protein Group G, therebycharacterizing the glatiramer acetate related drug substance or drugproduct of step (a).

In some embodiments of the present invention, the process wherein themammalian cells are THP-1 cells.

In some embodiments of the present invention, the process, wherein theincubation is for about 24 hours.

In some embodiments of the present invention, the process, whereincontacting the mammalian cells in step (b) comprises i) immunizing amammal with a predetermined amount of glatiramer acetate related drugsubstance or drug product, ii) preparing a culture of cells from themammal of step i) at one or more predetermined time points afterimmunization, and iii) incubating cells from the culture of cellsobtained from the mammal with an amount of the glatiramer acetaterelated drug substance or drug product of step (a), therebycharacterizing the glatiramer acetate related drug substance or drugproduct of step (a).

In some embodiments of the present invention, the process, wherein theglatiramer acetate related drug substance or drug product of step (iii)is the same glatiramer acetate related drug substance or drug product ofstep (i).

In some embodiments of the present invention, the process, wherein theglatiramer acetate related drug substance or drug product of step (iii)is a different glatiramer acetate related drug substance or drug productof step (i).

In some embodiments of the present invention, in a process for producinga drug product comprising a glatiramer acetate related drug substancewhich involves an array of testing, the improvement comprising includingin the array of testing the steps of:

-   a) characterizing the glatiramer acetate related drug substance    according to the process of any one of the above characterization    methods; and-   b) xxii) including the batch of the glatiramer acetate related drug    substance in the production of the drug product if the level of    expression of one or more proteins selected from the group    consisting of Protein Group A is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same    conditions; xxiii) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more proteins selected from the group    consisting of Protein Group B is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same    conditions; xxiv) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more proteins selected from the group    consisting of Protein Group C is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same    conditions; xxv) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more proteins selected from the group    consisting of Protein Group D is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same    conditions; xxvi) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more proteins selected from the group    consisting of Protein Group E is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same    conditions; xxvii) including the batch of the glatiramer acetate    related drug substance in the production of the drug product if the    level of expression of one or more proteins selected from the group    consisting of Protein Group F is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same conditions;    or xxviii) including the batch of the glatiramer acetate related    drug substance in the production of the drug product if the level of    expression of one or more proteins selected from the group    consisting of Protein Group G is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance under the same conditions.

In some embodiments of the present invention, in a process for releasinga drug product comprising a glatiramer acetate related drug substance,which process involves an array of testing, the improvement comprisingincluding in the array of testing the steps of:

-   a) characterizing the glatiramer acetate related drug product    according to the process of any one of the above characterization    methods; and-   b) xxii) releasing the batch of the glatiramer acetate related drug    product if the level of expression of one or more proteins selected    from the group consisting of Protein Group A is substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate related drug product under    the same conditions; xxiii) releasing the batch of the glatiramer    acetate related drug product if the level of expression of one or    more proteins selected from the group consisting of Protein Group B    is substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate related drug    product under the same conditions; xxiv) releasing the batch of the    glatiramer acetate related drug product if the level of expression    of one or more proteins selected from the group consisting of    Protein Group C is substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate related drug product under the same    conditions; xxv) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more    proteins selected from the group consisting of Protein Group D is    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate related drug    product under the same conditions; xxvi) releasing the batch of the    glatiramer acetate related drug product if the level of expression    of one or more proteins selected from the group consisting of    Protein Group E is substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate related drug product under the same    conditions; xxvii) releasing the batch of the glatiramer acetate    related drug product if the level of expression of one or more    proteins selected from the group consisting of Protein Group F is    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate related drug    product under the same conditions; or xxviii) releasing the batch of    the glatiramer acetate related drug product if the level of    expression of one or more proteins selected from the group    consisting of Protein Group G is substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug product under the same conditions.

In some embodiments of the present invention, in a process fordiscriminating between glatiramer acetate related drug substances ordrug products comprising the steps of:

-   a) characterizing one or more glatiramer acetate related drug    substances or drug products according to the process of any one of    the above characterization methods to obtain characteristics of each    of the glatiramer acetate related drug substances or drug products;-   b) obtaining characteristics of a glatiramer acetate drug substance    or drug product; and-   c) comparing the characteristics of the glatiramer acetate related    drug substances or drug products obtained in steps a) and b),    thereby discriminating between glatiramer acetate related drug    substances or drug products.

ADDITIONAL EMBODIMENTS OF THE INVENTION

In a process for producing a drug product comprising a glatirameracetate related drug substance, the improvement comprising the steps of:

-   a) characterizing the glatiramer acetate related drug substance    according to the process of any one of the above characterization    methods; and-   b) i) discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 1 is substantially identical to the level    of expression by the same type of cells in the absence of the    glatiramer acetate related drug substance under the same    conditions; ii) discarding the batch of the glatiramer acetate    related drug substance as unacceptable for inclusion in the drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 2 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; iii) discarding the batch of the glatiramer acetate    related drug substance as unacceptable for inclusion in the drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 3 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; iv) discarding the batch of the glatiramer acetate    related drug substance as unacceptable for inclusion in the drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 4 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; v) discarding the batch of the glatiramer acetate    related drug substance as unacceptable for inclusion in the drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 5 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; vi) discarding the batch of the glatiramer acetate    related drug substance as unacceptable for inclusion in the drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 6, is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; vii) discarding the batch of the glatiramer acetate    related drug substance as unacceptable for inclusion in the drug    product if the level of expression of one or more genes selected    from the group consisting of Gene Group 7, is downregulated or    substantially identical to the level of expression by the same type    of cells in the absence of the glatiramer acetate related drug    substance under the same conditions; viii) discarding the batch of    the glatiramer acetate related drug substance as unacceptable for    inclusion in the drug product if the level of expression of one or    more genes selected from the group consisting of Gene Group 8, is    upregulated or substantially identical to the level of expression by    the same type of cells in the absence of the glatiramer acetate    related drug substance under the same conditions; ix) discarding the    batch of the glatiramer acetate related drug substance as    unacceptable for inclusion in the drug product if the level of    expression of one or more genes selected from the group consisting    of Gene Group 9 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; x)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 10 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xi)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 11 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xii)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 12 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xiii)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 13 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xiv)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 14 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xv)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 15 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xvi)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 16 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xvii)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 17 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xviii)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 18 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xix)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 19 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xx)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 20 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxi)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 21 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxii)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 22 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxiii)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 23 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxiv)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 24 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxv)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 25 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxvi)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 26 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxix)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 29 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; or xxx)    discarding the batch of the glatiramer acetate related drug    substance as unacceptable for inclusion in the drug product if the    level of expression of one or more genes selected from the group    consisting of Gene Group 30 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions.

In a process for releasing a drug product comprising a glatirameracetate related drug substance, the improvement comprising the steps of:

-   a) characterizing the glatiramer acetate related drug product    according to the process of any one of the above characterization    methods; and-   b) i) discarding the batch of the glatiramer acetate related drug    product as unacceptable for release if the level of expression of    one or more genes selected from the group consisting of Gene Group 1    is substantially identical to the level of expression by the same    type of cells in the absence of the glatiramer acetate related drug    product under the same conditions; ii) discarding the batch of the    glatiramer acetate related drug product as unacceptable for release    if the level of expression of one or more genes selected from the    group consisting of Gene Group 2 is not substantially identical to    the level of expression by the same type of cells in the presence of    the glatiramer acetate drug product under the same conditions; iii)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 3 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug product    under the same conditions; iv) discarding the batch of the    glatiramer acetate related drug product as unacceptable for release    if the level of expression of one or more genes selected from the    group consisting of Gene Group 4 is not substantially identical to    the level of expression by the same type of cells in the presence of    the glatiramer acetate drug product under the same conditions; v)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 5, is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug product    under the same conditions; vi) discarding the batch of the    glatiramer acetate related drug product as unacceptable for release    if the level of expression of one or more genes selected from the    group consisting of Gene Group 6 is not substantially identical to    the level of expression by the same type of cells in the presence of    the glatiramer acetate drug product under the same conditions; vii)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 7, is    downregulated or substantially identical to the level of expression    by the same type of cells in the absence of glatiramer acetate drug    product under the same conditions; viii) discarding the batch of the    glatiramer acetate related drug product as unacceptable for release    if the level of expression of one or more genes selected from the    group consisting of Gene Group 8, is upregulated or substantially    identical to the level of expression by the same type of cells in    the absence of glatiramer acetate drug product under the same    conditions; ix) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 9 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug product under the same conditions; x)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 10 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug product    under the same conditions; xi) discarding the batch of the    glatiramer acetate related drug product as unacceptable for release    if the level of expression of one or more genes selected from the    group consisting of Gene Group 11 is not substantially identical to    the level of expression by the same type of cells in the presence of    the glatiramer acetate drug substance under the same    conditions; xii) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 12 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xiii)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 13 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xiv) discarding the batch of    the glatiramer acetate related drug product as unacceptable for    release if the level of expression of one or more genes selected    from the group consisting of Gene Group 14 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xv) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 15 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xvi)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 16 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xvii) discarding the batch of    the glatiramer acetate related drug product as unacceptable for    release if the level of expression of one or more genes selected    from the group consisting of Gene Group 17 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xviii) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 18 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xix)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 19 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xx) discarding the batch of the    glatiramer acetate related drug product as unacceptable for release    if the level of expression of one or more genes selected from the    group consisting of Gene Group 20 is not substantially identical to    the level of expression by the same type of cells in the presence of    the glatiramer acetate drug substance under the same    conditions; xxi) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 21 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxii)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 22 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xxiii) discarding the batch of    the glatiramer acetate related drug product as unacceptable for    release if the level of expression of one or more genes selected    from the group consisting of Gene Group 23 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxiv) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 24 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxv)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 25 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions; xxvi) discarding the batch of    the glatiramer acetate related drug product as unacceptable for    release if the level of expression of one or more genes selected    from the group consisting of Gene Group 26 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxix) discarding the batch of the glatiramer acetate    related drug product as unacceptable for release if the level of    expression of one or more genes selected from the group consisting    of Gene Group 29 is not substantially identical to the level of    expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; or xxx)    discarding the batch of the glatiramer acetate related drug product    as unacceptable for release if the level of expression of one or    more genes selected from the group consisting of Gene Group 20 is    not substantially identical to the level of expression by the same    type of cells in the presence of the glatiramer acetate drug    substance under the same conditions.

In one or more embodiments of the present invention, in a process foridentifying suboptimal activity of a glatiramer acetate related drugsubstance or drug product comprising the steps of:

-   a) administering a glatiramer acetate related drug substance or drug    product to a mammal;-   b) characterizing the glatiramer acetate related drug substance or    drug product according to the process of any one of the above    characterization methods; and-   c) i) identifying the glatiramer acetate related drug substance or    drug product as causing a suboptimal activity if the level of    expression of one or more genes selected from the group consisting    of Gene Group 1 is substantially identical to the level of    expression by the same type of cells in the absence of the    glatiramer acetate related drug substance or drug product under the    same conditions; ii) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 2 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance or drug product under the    same conditions; iii) identifying the glatiramer acetate related    drug substance or drug product as causing a suboptimal activity if    the level of expression of one or more genes selected from the group    consisting of Gene Group 3 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance or drug product under the    same conditions; iv) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 4 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance or drug product under the    same conditions; v) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 5 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance or drug product under the same    conditions; vi) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 6, is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate related drug substance or drug product under the    same conditions; vii) identifying the glatiramer acetate related    drug substance or drug product as causing a suboptimal activity if    the level of expression of one or more genes selected from the group    consisting of Gene Group 7, is downregulated or substantially    identical to the level of expression by the same type of cells in    the absence of the glatiramer acetate related drug substance or drug    product under the same conditions; viii) identifying the glatiramer    acetate related drug substance or drug product as causing a    suboptimal activity if the level of expression of one or more genes    selected from the group consisting of Gene Group 8, is upregulated    or substantially identical to the level of expression by the same    type of cells in the absence of the glatiramer acetate related drug    substance or drug product under the same conditions; ix) identifying    the glatiramer acetate related drug substance or drug product as    causing a suboptimal activity if the level of expression of one or    more genes selected from the group consisting of Gene Group 9 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance or    drug product under the same conditions; x) identifying the    glatiramer acetate related drug substance or drug product as causing    a suboptimal activity if the level of expression of one or more    genes selected from the group consisting of Gene Group 10 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance or    drug product under the same conditions; xi) identifying the    glatiramer acetate related drug substance or drug product as causing    a suboptimal activity if the level of expression of one or more    genes selected from the group consisting of Gene Group 11 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance    under the same conditions; xii) identifying the glatiramer acetate    related drug substance or drug product as causing a suboptimal    activity if the level of expression of one or more genes selected    from the group consisting of Gene Group 12 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xiii) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 13 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xiv)    identifying the glatiramer acetate related drug substance or drug    product as causing a suboptimal activity if the level of expression    of one or more genes selected from the group consisting of Gene    Group 14 is not substantially identical to the level of expression    by the same type of cells in the presence of the glatiramer acetate    drug substance under the same conditions; xv) identifying the    glatiramer acetate related drug substance or drug product as causing    a suboptimal activity if the level of expression of one or more    genes selected from the group consisting of Gene Group 15 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance    under the same conditions; xvi) identifying the glatiramer acetate    related drug substance or drug product as causing a suboptimal    activity if the level of expression of one or more genes selected    from the group consisting of Gene Group 16 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xvii) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 17 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xviii)    identifying the glatiramer acetate related drug substance or drug    product as causing a suboptimal activity if the level of expression    of one or more genes selected from the group consisting of Gene    Group 18 is not substantially identical to the level of expression    by the same type of cells in the presence of the glatiramer acetate    drug substance under the same conditions; xix) identifying the    glatiramer acetate related drug substance or drug product as causing    a suboptimal activity if the level of expression of one or more    genes selected from the group consisting of Gene Group 19 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance    under the same conditions; xx) identifying the glatiramer acetate    related drug substance or drug product as causing a suboptimal    activity if the level of expression of one or more genes selected    from the group consisting of Gene Group 20 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxi) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 21 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxii)    identifying the glatiramer acetate related drug substance or drug    product as causing a suboptimal activity if the level of expression    of one or more genes selected from the group consisting of Gene    Group 22 is not substantially identical to the level of expression    by the same type of cells in the presence of the glatiramer acetate    drug substance under the same conditions; xxiii) identifying the    glatiramer acetate related drug substance or drug product as causing    a suboptimal activity if the level of expression of one or more    genes selected from the group consisting of Gene Group 23 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance    under the same conditions; xxiv) identifying the glatiramer acetate    related drug substance or drug product as causing a suboptimal    activity if the level of expression of one or more genes selected    from the group consisting of Gene Group 24 is not substantially    identical to the level of expression by the same type of cells in    the presence of the glatiramer acetate drug substance under the same    conditions; xxv) identifying the glatiramer acetate related drug    substance or drug product as causing a suboptimal activity if the    level of expression of one or more genes selected from the group    consisting of Gene Group 25 is not substantially identical to the    level of expression by the same type of cells in the presence of the    glatiramer acetate drug substance under the same conditions; xxvi)    identifying the glatiramer acetate related drug substance or drug    product as causing a suboptimal activity if the level of expression    of one or more genes selected from the group consisting of Gene    Group 26 is not substantially identical to the level of expression    by the same type of cells in the presence of the glatiramer acetate    drug substance under the same conditions; xxix) identifying the    glatiramer acetate related drug substance or drug product as causing    a suboptimal activity if the level of expression of one or more    genes selected from the group consisting of Gene Group 29 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance    under the same conditions; or xxx) identifying the glatiramer    acetate related drug substance or drug product as causing a    suboptimal activity if the level of expression of one or more genes    selected from the group consisting of Gene Group 30 is not    substantially identical to the level of expression by the same type    of cells in the presence of the glatiramer acetate drug substance    under the same conditions.

The Additional Embodiments described above can be readily applied andpracticed with features of Embodiments of the Invention described in thesection preceeding the Additional Embodiments.

For example, in a process for producing a drug product comprising aglatiramer acetate related drug substance, where the batch of theglatiramer acetate related drug substance is included in the drugproduct if the level of expression of one or more genes selected fromone or more Gene Groups is substantially upregulated relative to thelevel of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions,then conversely the batch of the glatiramer acetate related drugsubstance is discarded if the level of expression of one or more genesselected from one or more Gene Groups is not substantially upregulatedrelative to the level of expression by the same type of cells in theabsence of the glatiramer acetate related drug substance under the sameconditions as unacceptable for inclusion in the drug product.

DEFINITIONS

As used herein, a “naïve human” is a human that has not been treatedwith any multiple sclerosis drug.

As used herein, a “glatiramoid naïve human” is a human that has not beentreated with any glatiramoid drug. A glatiramoid naïve human could havebeen treated with another multiple sclerosis drug.

As used herein, “in the blood of” is represented by peripheral bloodmononuclear cells (PBMCs), lymphocytes, monocytes, macrophages,basophils, dendritic cells or other cells derived from a mammal's blood.

As used herein, a “reference standard” is a sample or value which servesas a point of comparison for another sample or value which differs fromthe reference standard with respect to one or more variables. Withspecific regard to a human, a “reference standard” is a value or rangeof values that characterizes a defined population in a defined state ofhealth. For example, a reference standard can characterize a healthyhuman or a human afflicted with multiple sclerosis, and when the humanis afflicted with multiple sclerosis the human can be naïve or havingreceived glatiramer acetate drug substance.

As used herein, the term “glatiramer acetate related drug substance”(GARDS) is intended to include include polypeptides with a predeterminedsequence as well as mixtures of polypeptides assembled from the fouramino acids glutamic acid (E), alanine (A), lysine (K), and tyrosine(Y); from any three of the amino acids Y, E, A and K, i.e. YAK, YEK, YEAor EAK; or from three of the amino acids Y, E, A and K and a fourthamino acid. Examples of glatiramer acetate related polypeptides aredisclosed in U.S. Pat. Nos. 6,514,938 A1, 7,299,172 B2, 7,560,100 and7,655,221 B2 and U.S. Patent Application Publication No. US 2009-0191173A1, the disclosures of which are hereby incorporated by reference intheir entireties. Glatiramer acetate related substances includeglatiramoids.

As used herein, a “glatiramer acetate related drug product” (GARDP)contains a glatiramer acetate related drug substance.

As used herein, a “glatiramer acetate related drug substance or drugproduct” is a glatiramer acetate related drug substance or a glatirameracetate related drug product.

As used herein a “glatiramoid” is a complex mixture of syntheticproteins and polypeptides of varying sizes assembled from four naturallyoccurring amino acids: L-glutamic acid, L-alanine, L-lysine, andL-tyrosine, in a defined molar ratio. Examples of glatiramoids includeglatiramer acetate drug substance (e.g. Copaxone®) as well asglatiramoids other than Copaxone®, e.g. GA-Natco.

As used herein, a “glatiramer acetate drug substance” (GADS) isglatiramer acetate produced by Teva Pharmaceutical Industries, Ltd. andis the active ingredient in a glatiramer acetate drug product.

As used herein, a “glatiramer acetate drug product” (GADP) contains aglatiramer acetate drug substance produced by Teva PharmaceuticalIndustries, Ltd. which consists of the acetate salts of syntheticpolypeptides, containing four naturally occurring amino acids:L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an averagemolar fraction of 0.141, 0.427, 0.095, and 0.338, respectively, and hasan average molecular weight of 5,000-9,000 daltons. (8) Copaxone® is aglatiramer acetate drug product.

As used herein, a “glatiramer acetate drug substance or drug product” isa glatiramer acetate drug substance or a glatiramer acetate drugproduct.

As used herein a “glatiramer acetate reference standard” is or containsthe drug substance found in a glatiramer acetate drug product.

As used herein “suboptimal activity” refers to a negative response or toa response which is less than the response to glatiramer acetate drugsubstance or glatiramer acetate drug product produced by TevaPharmaceutical Industries, Ltd.

As used herein, “release” of a drug product refers to making the productavailable to consumers.

As used herein, “about” with regard to a stated number encompasses arange of +10 percent to −10 percent of the stated value. By way ofexample, about 100 mg therefore includes the range 90-110 mg andtherefore also includes 90, 91, 92, 93, 94, 95 96, 97, 98, 99, 100, 101,102, 103, 104, 105, 106, 107, 108, 109 and 110 mg. Accordingly, about100 mg includes, in an embodiment, 100 mg.

As used herein, “hematological cell” comprises neutrophils,erythrocytes, basophils, monocytes, eosinophils, platelets, lymphocytes,and splenocytes.

As used herein, an “array of testing” for a glatiramer acetate relateddrug substance or drug product includes, but is not limited to, anyanalytical method test such as in vitro tests or molecular weight tests,biological assays such as the ex vivo tests and clinical efficacy testswhich characterize the GARDS or GARDP, or clinical trials. Examples oftesting for a glatiramer acetate related drug substance or drug productare disclosed in U.S. Patent Application Publication Nos. US2012-0309671 and US 2011-0230413, and in PCT International ApplicationPublication Nos. WO 2000/018794, WO 2012/051106, WO 2013/055683, WO2014/058976, the disclosures of which are hereby incorporated byreference in their entireties.

It is understood that where a parameter range is provided, all integerswithin that range, tenths thereof, and hundredths thereof, are alsoprovided by the invention. For example, “0.2-5 mg” is a disclosure of0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg etc. up to 0.3 mg, 0.31 mg, 0.32 mg,0.33 mg etc. up to 0.4 mg, 0.5 mg, 0.6 mg etc. up to 5.0 mg.

All combinations of the various elements described herein are within thescope of the invention.

It is understood that where “at least one” or “one or more” is recitedalong with a list, then 1, 2, 3, 4 . . . or all members of that list aredisclosed in every combination. For example, in a group of 43 genes, “atleast one” and “one or more” is a disclosure of one gene, two genes,three genes, etc., in any combination, up to the forty three genes.

As used herein, “characterization” or “characterizing” is understood toinclude obtaining information which was produced in the same location orcountry, or a different location or country from where any remainingsteps of the method are performed.

As used herein, processes of producing a glatiramer acetate related drugsubstance or drug product are known in the art. Examples of suchmanufacturing processes are disclosed in U.S. Pat. No. 5,800,808, and inPCT International Application Publication Nos. WO 2005/032553, WO2005/032395, WO 1999/22402, the disclosures of which are herebyincorporated by reference in their entireties.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as described more fully in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS Methods

The null hypothesis in traditional gene-expression studies, includingTeva's studies with the glatiramoids, is that there are no significantgene expression differences induced between the treatments. As such, theexpectation is that regardless of the biological system used fortesting, genes would show no statistically significant, nor biologicallymeaningful differences among the various treatments. Only in cases wherethe treatments induce significant observable effects, genesdifferentially expressed between treatments will pass the stringentstatistical tests, and false discovery rate (FDR) correction formultiple hypotheses (Benjamini and Hochberg, 1995). These stringentrequirements were imposed a priori across all tests to ensure robustnessof results and minimizing of spurious findings. Such statisticallysignificant differences, if biologically meaningful (i.e., related tothe disease biology or any of the drug's known or putative targets anddownstream pathways), warrant further studies, as two drugs that haveidentical activities in biological systems should not inducestatistically observable and biologically enriched differences whencompared against each other.

These studies were not designed to establish a particular set of genesin a specific model system as a panel to evaluate sameness betweendifferently manufactured glatiramoids. Instead, these were designed toassess the degree of similarity in the impact of two glatiramoids onrelevant biological pathways. The application of robust methodology(high number of replicates, conditions and time-points, where relevant)was aimed to describe pathways changed by different treatments out ofthe entire milieu of genomic patterns. The results obtained across thetested experimental models revealed statistically significantdifferences between drugs, which were intended to be similar and toperform the same function, despite stringent statistical thresholdrequirements. This was noteworthy particularly in genes highly relevantto disease processes and drug response mechanisms. In addition, thedifferences observed revealed a complex interplay between immunologicalpathways, such that some differences were common to multiple systems,while many others were dependent on the specific model system (forexample, some key genes modulated in T cells were not the same as inmonocytes). This is not surprising for a process that involvesmultifaceted interactions between many immune system components, and isalso exemplified in experimental studies of Copaxone®'s mechanism ofaction. Thus, no single model system, characterization method, or set ofgenes tested was sufficient to comprehensively capture the differencesbetween the drugs. These observations indicate a need for in-depthinvestigation of comparative gene expression profiles in severalrelevant pre-clinical systems as key indicators of similarity and/orsameness between generic candidates and the original drug within thecontext of Non-Biological Complex Drugs (NBCD). Ideally, the concordancebetween high-resolution physicochemical measures (e.g. ion motility massspectrometry, IMMS), gene expression profiling and clinical trials wouldallow a more definitive assessment of equivalence in terms of patientbenefit and safety.

Mice

All experimental procedures conformed to accepted ethical standards foruse of animals in research and were in accordance with Committee for theCare and Use of Experimental Animals guidelines and approved by the TevaInstitutional Animal Care and Use Committee.

Preparation of Mouse Spleen Cell Cultures

All experimental procedures conformed to accepted ethical standards foruse of animals in research and were in accordance with Committee for theCare and Use of Experimental Animals guidelines and approved by the TevaInstitutional Animal Care and Use Committee.

Mouse Splenocytes: Gene Expression Analysis

In the first of the genomic studies, 8- to 12-week old female mice (N=8)of the (Balb/c x SJL) F1 variety (Harlan, Israel) were injectedsubcutaneously with glatiramer acetate (GA) in order to induce specificGA-reactive T cells as would be present in a Copaxone® treated patient.

After 3 days, the mice were sacrificed and cells from their spleens(splenocytes) were isolated because such cells are representative of,and commonly utilized as a gold standard to study the immune system. Theaqueous activator samples, mannitol (the non-active excipient inCopaxone® and all other marketed proposed generics) and medium were usedas negative controls.

Given the robustness of the model established in our first mousesplenocyte study, we sought to expand the scope of the investigationusing the exact same study design, but with an expanded set oftreatments (FIG. 1). In addition to comparing Copaxone® to a purportedforeign generic version, we also sought to compare purported genericsfrom various manufacturers to each other. Using the mouse splenocyteprocedure described herein, we generated expression data in response toactivation with proposed generic glatiramer acetate samples from Escadra(Argentina), Probioglat (Mexico; Probiomed), and Hangzhou (China: API).A total of 21 samples of Copaxone® from 21 different batches were used,along with 10 samples from 2 lots of Escadra, 12 samples from 4 batchesof Natco, 4 samples from 1 batch of Probioglat, 5 samples of Hangzhoufrom 2 batches, 12 samples of GA-RS from 1 batch, and 8 samples ofmedium.

Mouse Splenocytes: RNA Isolation and Microarray Expression Profiling

Extraction of total RNA from activated splenocytes was extracted usingPerfectPure RNA Cultures CEKK kit 50 (5Prime GmbH, Hamburg, Germany) andfollowing the manufacturer's instructions. RNA quality was assessedusing the absorbance ratio at 260/280 nm and gel electrophoresis(Experion, Bio-Rad, Hercules, Calif., USA). Total RNA extracted fromsamples was hybridized to Illumina Mouse WG-6V2 microarray chipscontaining more than 45,200 transcripts.

Samples were randomized on the chips to avoid batch effects. Illumina'sBeadStudio software was utilized for image processing, quantification ofsignal intensity per bead, and background signal correction. Multipleprobes were analyzed for a given gene were averaged and batch correctionwas conducted using Partek. Further analysis was conducted individuallywithin the context of known pathways, and batch correction was conductedusing ComBat, as implemented in the SVA R package sva: SurrogateVariable Analysis. Available:www.bioconductor.org/packages/release/bioc/html/sva.html). Briefly,ComBat is an empirical Bayesian approach utilizing location and scalemetrics across several genes to adjust for batch effects in datasets,even datasets containing small sample sizes. Treatment labels were addedas covariates to the batch correction in order to preserve relevanttreatment effects. Principal Component Analysis (a multivariateapproach) showed that the main effect in the first principal componentremained due to treatment effects after batch correction.

Mouse Splenocytes: Gene Expression Analysis—Polimunol versus Copaxone®Gene Expression Studies

Mice

All experimental procedures conformed to accepted ethical standards foruse of animals in research and were in accordance with Committee for theCare and Use of Experimental Animals guidelines and approved by the TevaInstitutional Animal Care and Use Committee. For these experiments, 8-to 12-week-old female (Balb/c X SJL) F1 mice (Janvier, France) werepurchased. Mice were kept at 21±3° C.; the relative humidity was 30-70%,the light/dark cycle was 12/12 h. Animals were maintained on a standardrodent pellet diet and sterile filtered tap water available ad libitum.

Preparation of Mouse Spleen Cell Cultures

To stimulate induction of GA-reactive T cells, twelve mice were injectedwith 100 μL of a 2.5 mg/mL solution of GA reference standard (GA-RS) inphosphate-buffered saline (250 μg GARS per mouse). GA-RS (Teva) is aselected GA drug substance batch defined as the standard batch and usedas a reference in quality control release tests of all Copaxone®batches. Another group of twelve mice were injected with 100 μL of a 2.5mg/mL solution of Polimunol in phosphate-buffered saline (250 μgPolimunol per mouse). Polimunol is a proposed generic manufactured acompany other than Teva. Mice were housed for 3 days after immunization;mice were then sacrificed and their spleens were aseptically removed andplaced on ice in RPMI 1640. A single cell suspension was prepared. Afterred blood cells lysis, splenocytes from the same immunization group werepulled and resuspended to a final concentration of 10×106 cells/mL indefined cell culture media (DCCM1) (Biological Industries, Beit Haemek,Israel) (96.7% v/v) enriched with L-glutamine 2 mM (1% v/v), MEMNon-Essential Amino Acids 2 mM (1% v/v), sodium pyruvate 1 mM (1% v/v),antibiotic/antimycotic solution (0.2% v/v) and 2-mercaptoethanol 50 mM(0.1% v/v).

In Vitro Cell Activation

Splenocytes were treated with activator samples diluted in medium (125μL per well of 80 μg/mL solutions, final concentration in the well: 40μg/mL) of: i) 3 different batches of GA drug product manufactured byTeva ii) one batch of proposed generic (Polimunol). Polimunol is aproduct marketed as generic GA and manufactured by a company other thanTeva (i.e. Synthon). The activator samples, mannitol (the nonactiveexcipient in Copaxone®), and medium were added to 96-well tissue cultureplates (three wells per sample). Splenocytes (125 μL 10×10⁶ SPL cell/mLsuspension) were added to the activator solutions. Each activator samplewas loaded in two different plates. One for the cells from miceimmunized with GA and one for cells from mice immunized with proposedgeneric. Plates were incubated for 24 h at 37° C. Cells were collectedfrom the wells and were centrifuged at 300 g for 5 minutes. Supernatantswere aspirated and cell pellets were resuspended in RLT buffer (fromRNeasy mini kit of Qiagen, Cat #74106) for cell lysis. The cell lysateswere centrifuged and supernatants were collected and frozen at −70° C.Samples were sent for further processing.

Analysis Methods

For additional detail on experimental methods used in mouse studies,please refer to publications [Bakshi et al; Towfic et al]. Note that inthis study, mice were immunized with either Copaxone® or Polimunol, andsubsequently splenocytes were isolated and treated ex vivo withCopaxone® or Polimunol. RNA was extracted and expression profiled acrossthe entire genome using the Affymetrix Mouse Genome 430 2 chip. Threelots of Copaxone®, and one lot of Polimunol were comparatively tested insix replicates each.

Outlier Identification and Normalization

Outlier samples were identified using the R package ArrayQCMetrics andexcluded from further data processing steps. A sample was considered anoutlier if it failed more than half of the included tests either beforeor after RMA normalization. Data were RMA normalized using the Affy Rpackage.

Batch Correction

Correction for batch variation was performed using ComBat as describedabove (THP-1 methods). Date of microarray experiment was used as batch,and the combination of treatment and immunization was used as covariate.Principal Component Analysis (a multivariate approach) showed that themain effect in the first principal component remained due to treatmenteffects after batch correction.

Differential Expression Analysis

Differentially expressed probesets were identified across conditionsusing linear models for microarray data (LIMMA; Smyth, G. K. (2004)), astandard R Bioconductor package. Linear models and empirical Bayesmethods for assessing differential expression in microarray experiments.Statistical Applications in Genetics and Molecular Biology 3, No. 1,Article 3). To compare GA and purported generic, comparisons werecorrected to compare each treatment relative to mannitol control (e.g.,[GA vs mannitol] was compared via LIMMA to [Polimunol vs mannitol]).Probesets were filtered by MAS5 calls of presence on the chip (to beconsidered present, a probeset was required to have on average a call ofpresent or marginal across samples). Probesets were mapped to genesusing the annotation available for the Mouse 430 2 chip from Affymetrix.Unless otherwise noted, FDR adjusted p values reported for genesrepresent the lowest FDR adjusted p value for present probesets for thatgene.

Pathway Enrichment Analysis

Upregulated and downregulated probesets were analyzed separately forpathway enrichment, using DAVID (Huang et al, Nucleic Acids Res 2009).Pathway enrichment results were visualized using volcano plots, plottingeither −log adjusted p values or untransformed adjusted p values versusenrichment scores for the pathways. For comparisons between branded GAand Polimunol, upregulated or downregulated probesets with FDR-adjustedp values<0.05 and fold changes (FC) with absolute value greater than 1.2were used for pathway enrichment. For comparisons between branded GA andmannitol, upregulated or downregulated probesets with FDR-adjusted pvalues<0.05 and FC with absolute value greater than 2 were used forpathway enrichment. DAVID runs were conducted in December 2014 andJanuary 2015.

Human Monocyte Cell Line: Gene Expression Analysis

THP-1 human monocytes (TIB-202) were purchased from ATCC®. Cells weremaintained in recommended RPMI-1640 media containing FCS, L-Glutamine,Sodium Pyruvate, D-Glucose, HEPES, and 2-mercaptoethanol at 37° C. and5% CO2. Prior to treatment cells were passed and plated in a 6-wellplate at a concentration of 1.0×10⁶ cells/mL. Cells were allowed torecover for four hours after passage (prior to treatment). Using apredetermined non toxic concentration the cells were spiked with 50μg/mL of either Copaxone®, GA/RS, Escadra, Probioglat, and Natco, and100 μg/mL mannitol was spiked as a negative control (vehicle). Eachsample was analyzed in six replicates. Cells were treated for 6, 12, and24 hours. Following treatment time cells were lysed using a Qiagen®based lysis kit. Prior to RNA isolation samples were randomized in orderto avoid batch effect. Total RNA was isolated using Qiagen® RNeasy kit.RNA quality was assessed by determining the absorbance ratio 260/280 nmas well as electrophoresis bioanalyzer with 260/280 ratio of 1.9-2.1 andRIN of above 9 were deemed acceptable. Gene expression was measuredusing Affymetrix® U133 plus 2.0 format. Sample processing was executedaccording to established manufacturer protocols. The scheme in (FIG. 2)illustrates the general experimental outline.

Human Monocyte Cell Line: RNA Isolation and Microarray ExpressionProfiling

RNA from THP-1 cells was extracted and expression profiled across theentire genome using the Affymetrix Human Genome U133 Plus 2.0 chip,interrogating a total of over 47,000 transcripts. Four batches ofCopaxone® and one batch of Probioglat were comparatively tested in sixbiological replicates each. Key identified genes were independentlyevaluated for level of gene expression by quantitative Real-Time PCR ofsamples collected in the same experiments.

Methods for Studies Using MS Patient Data

Patient studies utilized a subset of MS patients treated with Copaxone®from FORTE clinical trial with time-series PBMC expression profiling.Timepoints of 0, 1, 2, 3 months were used. The study included 9 patientsfor a total of 36 samples.

Repeated-Measures ANOVA

ANOVA was run taking into account multiple timepoints from each patient.Variability within patients across timepoints was taken into account inthe p value calculation.

qRT-PCR Analysis

Key genes identified by differential expression analysis were assayedusing qRT-PCR. RNA was utilized from each of 6 biological samples foreach treatment (Copaxone® and Probioglat) and 15 technical replicateswere performed for each sample (a total of 90 observations pertranscript per treatment). Since three Copaxone® batches and oneProbioglat batch were available, a total of 360 observations from eachtranscript were evaluated. To evaluate the data, the 2^(−ΔΔct)approximation was utilized with GAPDH as reference transcript andvehicle control (mannitol) as calibrator. A one-sided t-test withunequal variance was used to compare the RNA expression from the twotreatments.

Human Monocyte Cell Line: Gene Expression Analysis—Polimunol versusCopaxone® Gene Expression Studies

Experimental Design

Cells from a human monocyte cell line (THP-1) were stimulated witheither branded glatiramer acetate—Copaxone®, or the purported genericPolimunol, or vehicle control (mannitol) for 6 hours. RNA was extractedand expression profiled in a blinded fashion across the entire genome,using the Affymetrix Human Genome U133 Plus 2.0 chip, interrogating atotal of over 47,000 transcripts. Three lots of Copaxone® (148, 164,166) and one lot of Polimunol (XBN) were comparatively tested in sixreplicates each. This entire experiment was performed independentlytwice, using an identical study design, reagents and compounds by thesame technicians on two separate days; resulting in twelve replicatestotal per condition.

A Priori Power Analysis

Using the R statistical package ssize.fdr, power calculations wereperformed to determine the number of samples needed to detectdifferentially expressed genes with a fold-change between treatments ofas low as 1.3 with 80% power. Based on the results of these powercalculations, the experiment was designed to include six replicates ofeach condition. The order in which the samples were processed wasrandomized with respect to treatment and stimulation time in order toavoid creating confounding batch effects.

Outlier Identification and Normalization

Outlier samples were identified using the R package ArrayQCMetrics andexcluded from further data processing steps. A sample was considered anoutlier if it failed more than half of the included tests either beforeor after RMA normalization. Data were RMA normalized using the Affy Rpackage.

Batch Correction

Correction for batch variation was performed using ComBat (Johnson etal, Biostat, 2007), as implemented in the SVA R package (Leek J T,Johnson W E, Parker H S, Jaffe A E, Storey J D (2013) sva: SurrogateVariable Analysis. Available:www.bioconductor.org/packages/release/bioc/html/sva.html). Briefly,ComBat is an empirical Bayesian approach utilizing location and scalemetrics across several genes to adjust for batch effects in datasets,even datasets containing small sample sizes. Date of experiment wasutilized as batch. Treatment labels were added as covariates to thebatch correction in order to preserve relevant treatment effects.Principal Component Analysis (a multivariate approach) showed that themain effect in the first principal component remained due to treatmenteffects after batch correction.

Treatment labels were added as covariates to the batch correction topreserve relevant treatment effects. Principal Component Analysis showedthe main effect in PC1 remained due to treatment effects after batchcorrection (FIG. 43).

Differential Expression Analysis

Differentially expressed probesets were identified across conditionsusing linear models for microarray data (LIMMA; Smyth, G. K. (2004)), astandard R Bioconductor package. Linear models and empirical Bayesmethods for assessing differential expression in microarray experiments.Statistical Applications in Genetics and Molecular Biology 3, No. 1,Article 3). To compare Copaxone® and a purported generic, comparisonswere corrected to compare each treatment relative to mannitol control(e.g., [GA vs mannitol] was compared via LIMMA to [purported generic vsmannitol]). For use in pathway analyses, probesets were filtered by MAS5calls of presence on the chip for the relevant samples in the comparison(e.g., to be considered present, a probeset was required to have onaverage a call of present or marginal across samples). An additional QCstep was performed to remove probesets determined to be highly variablebetween multiple THP-1 datasets, as follows: a probeset was deemedhighly variable if across three THP-1 studies to date, that probeset wasobserved to be upregulated, downregulated, and not modulated by Copaxoneacross the three studies. This criterion resulted in filtering out 216probesets. Probesets were mapped to genes using the annotation availablefor the U133 Plus 2.0 chip from Affymetrix. FDR adjusted p valuesreported for genes represent the lowest FDR adjusted p value for presentprobesets for that gene.

Pathway Enrichment Analysis

Upregulated and downregulated probesets were analyzed separately forpathway enrichment, using DAVID (Huang et al, Nucleic Acids Res 2009).Pathway enrichment results were visualized using volcano plots, plotting−log p values versus enrichment scores. For comparisons between Copaxoneand Polimunol, upregulated or downregulated probesets with FDR-adjustedp values<0.05 and fold changes (FC) with absolute value greater than 1.1were used for pathway enrichment. For comparisons between Copaxone® andmannitol, upregulated or downregulated probesets with FDR=adjusted pvalues<0.05 and FC with absolute value greater than 1.3 were used forpathway enrichment. DAVID runs were conducted December 5 and 10, 2014.

Protein Concentrations

THP-1 cells were activated with GA or Probioglat as described above. Thesupernatant (1.0 mL of cell culture media) was collected at the 24 hourtimepoint (to account for the time duration required for translationrelative to the 6 hour mRNA data reported herein).

A Luminex assay was utilized to measure the concentrations of a panel of45 chemokines and cytokines (in pg/ml) using Bio-Plex Human Chemokine(Bio Rad kit) and Luminex Performance Assay (R&D kit). Three of thegenes that were found to significantly differ between GA and Probioglatby qRT-PCR (CXCL10, MMP9, and CCL5/RANTES) had corresponding proteinspresent in the Luminex panel. In addition, two other genes that werefound to differ significantly between GA and Probioglat using thegenome-wide microarray mRNA data were also present in the Luminex panel(CCL2, IL10).

To calculate the fold change between the protein expression levels withProbioglat and with GA, the values for the four GA batches were averagedtogether and compared to the value for Probioglat (Probioglat expressionlevel/average GA expression level).

Primary Human Monocyte Study

50 mL of blood was obtained from a healthy donor, and CD14+ cells wereseparated from whole blood using magnetic beads (Miltenyi Biotech).Purity was determined by FACS analysis using the following antibodies:CD14, CD15, CD16, CD45 (BD Biosciences). Into each plate of the 6 wellplate 0.5 mL containing 1.0×10⁶ cells was added. In addition 0.5 mL ofeither Copaxone, Probioglat (100 μg/mL) or mannitol (200 μg/mL) wasadded, total volume in each well was 1 mL. Final concentration ofCopaxone and Probioglat was 50 μg/mL and mannitol final concentrationwas 100 μg/mL. Cells were incubated for 6 hours at 37° C. at 5% CO₂followed by centrifugation to pellet the cells. The cell pellets werethen processed using a Qiagen RNeasy RNA purification protocol.

Expression levels of nine genes were measured using RT-PCR with GAPDH asreference transcript. Analyses reported compared Probioglat samples toGA samples as calibrator. Similar results were obtained when usingmannitol as reference (i.e., the same set of genes were significantlyupregulated in Probioglat relative to Copaxone). Differences inexpression levels were evaluated for significance using one-sidedt-tests with unequal variance.

Example 1 Analysis of Time-sensitive Modulation of Genes by Copaxone®Treatment in TRP-1 Monocyte Cell Line

Three time points were tested to identify the time point reflecting thegreatest impact of treatment in each model system. Examining the numberof genes modulated by Copaxone® relative to the mannitol control, the 6hour time point demonstrated the largest number of genes significantlymodulated by Copaxone® (6,890 with an FDR-adjusted p<0.05), over 2-foldmore than at 12 hours (3,118 with FDR-adjusted p<0.05) and nearly 4-foldmore than at 24 hours (1,791 with FDR-adjusted p<0.05) (Table 1).Subsequent analyses focused on the 6 hour time point, as the time pointreflected the greatest impact of treatment in this model system.

TABLE 1 Numbers of genes significantly modulated by GA treatment inTHP-1 monocyte cell line at each timepoint 6 hr 12 hr 24 hr Up- Down-Up- Down- Up- Down- regu- regu- regu- regu- regu- regu- lated latedlated lated lated lated nominal 3511 4909 2377 3430 1410 3724 p < 0.05FDR 2824 4066 1308 1810 606 1185 p < 0.05 FDR 257 119 68 10 15 0 p <1e−5, |FC| >= 1.5 FDR 557 508 210 50 57 6 p < 1e−5, |FC| >= 1.3 *FC—Fold Change; FDR—False Discovery Rate correction

GA Mechanism of Action

To gain insight into GA's MOA, the effect of GA treatment on THP-1 humanmonocytes was examined, since as discussed above, antigen-presentingcells in general, including monocytes in particular, have been shown tobe involved in GA treatment effects (Weber et al., Nat. Med. 2007; Kimet al, J. Immunol. Batim. Md. 2004; Burger et al., Proc. Natl. Acad.Sci. 2009; Smyth, Stat. Appl. Genet. Mol. Biol. 2004; Comi et al.,Neurol. Barc. Spain 2002). In particular, the THP-1 cell line has beenused to examine GA effects (Rizvi et al., Int. J. Nanomedicine, 2006).In addition, genes associated with monocytes in particular havepreviously been shown to be differentially expressed following treatmentwith a purported generic marketed by Natco in India, as compared withCopaxone (Huang et al., Nucleic Acids Res. 2009).

mRNA expression levels were compared between GA and control (mannitol)tested with 6 sample replicates for each of 4 batches of GA and formannitol, using LIMMA (Sim et al., Nat. Biotechnol. 2011) (Methods).Many genes were modulated significantly (FDR-adjusted p-value<0.05) ateach timepoint by treatment with branded GA (Table 1; Table 2 lists topmodulated probesets). For example, at 6 hours of GA treatment, 2824genes were significantly increased in expression (here termedupregulated) by FDR-adjusted p-value<0.05 (3511 genes by nominalp-value<0.05) and 4066 genes were significantly decreased in expression(here termed downregulated) by FDR-adjusted p-value<0.05 (4909 genes bynominal p-value<0.05). Fewer genes were significantly modulated astreatment time increased, with approximately half as many modulated at12 hours, and approximately one-quarter at 24 hours (Table 1). We chose6h for initial downstream analysis since this timepoint reflects thegreatest impact of treatment. Levels of GA persisted in the cell culturemedium in the range of 44-52 μg/mL over 24 hours (FIG. 3), indicatesthat this observation is unlikely to reflect a decrease in concentrationof drug. Rather, this decrease in number of genes affected from early tolater timepoints represents an attribute of the response of the cells tothe drug.

GA impacts expression most pronouncedly at 6h (Table 2). The use of thisearly timepoint may also be biologically relevant given that GA isthought to be rapidly degraded at the injection site, eventually withoutmeasurable blood levels (Vieira et al., J. Immunol. Baltim. Md 1950,2003; Thamilarasan et al., J. Neuroinflammation 2013; Comi et al, Neurol2002, Rizvi et al, Int J Nanomed 2006).

The differentially expressed genes included several anti-inflammatorygenes. For instance, IL10, the gene encoding the anti-inflammatorycytokine IL-10, was increased in expression (upregulated) at the 6 hourtimepoint (FDR adjusted p value 3.1e-9; fold change (FC) 1.52; FIG. 4a). Expression of IL1RN, encoding IL-1ra, a protein that inhibits theactivities of the pro-inflammatory cytokines IL-1a and IL-1b, wasincreased (upregulated) at all three timepoints. FIG. 4b-d shows the 6htimepoint for all present probesets (FDR adjusted p values 6.7e-16,1.7e-10, and 1.2e-9, and FC 1.43, 1.35, and 1.26, respectively).

To determine whether the differentially-expressed genes related to oneanother in a coordinated fashion, top significantly up- anddown-regulated genes were examined for pathway enrichment using DAVID asdescribed in Methods (FIG. 5; Table 5). The top genes significantlyupregulated by Copaxone in the human THP-1 cell line at 6 hours oftreatment were enriched significantly (by Benjamini corrected pvalue<0.05) for 114 pathways (Table 5), including many immune-relatedpathways (FIG. 5). For example, the regulation of immune system process(GO:0002682) and cytokine-cytokine receptor interaction (hsa04060)pathways were both significantly enriched among the top upregulatedgenes. The top upregulated genes identified as members of thecytokine-cytokine receptor interaction pathway (hsa04060) are shown inFIG. 6. In addition, 9 pathways were significantly enriched among genesdownregulated by GA (Table 5).

TABLE 2 Human monocyte study: probesets significantly modulated byCopaxone ® relative to mannitol at 6 hours, subject to fold-change andadjusted p value filters of 1.5 and 1e−5 ID Gene raw.FC AveExpr P.Valueadj.P.Val Upregulated: 201005_at CD9 3.77232321 10.8126963 1.14E−346.23E−30 206835_at STATH 7.52573433 10.4825707 1.00E−33 2.74E−291553982_a_at RAB7B 2.26468475 11.7452289 1.26E−31 2.30E−27 242871_atPAQR5 3.9374814 9.90015385 7.51E−31 1.01E−26 1555759_a_at CCL52.21501539 13.5769189 9.21E−31 1.01E−26 228766_at — 2.3291844 10.55597173.35E−30 3.06E−26 209555_s_at CD36 2.44281389 9.32514677 7.64E−295.66E−25 203939_at NT5E 5.3338766 8.32269063 8.29E−29 5.66E−25 208789_atPTRF 2.82016222 9.15275301 1.88E−28 1.14E−24 230266_at RAB7B 2.2382489111.7520076 2.34E−28 1.28E−24 206488_s_at CD36 2.15872949 10.88683743.67E−28 1.83E−24 208121_s_at PTPRO 2.14699192 9.81795145 4.30E−281.96E−24 203037_s_at MTSS1 3.1858517 11.4020576 7.89E−28 3.32E−241405_i_at CCL5 2.29122708 13.3028093 2.79E−27 1.06E−23 204655_at CCL52.25036905 13.1626051 2.90E−27 1.06E−23 206171_at ADORA3 2.1003654910.0753041 3.42E−27 1.17E−23 219386_s_at SLAMF8 2.98872777 10.03027193.80E−27 1.22E−23 226218_at — 3.50148157 7.21345525 1.83E−26 5.55E−23218559_s_at MAFB 2.64025573 12.4234341 3.40E−26 9.78E−23 223125_s_atC1ORF21 2.21866076 11.0023707 4.15E−26 1.13E−22 203887_s_at THBD1.79337816 12.8191102 4.45E−26 1.15E−22 227265_at KIAA1505 2.503210699.85031558 4.61E−26 1.15E−22 205495_s_at GNLY 2.40116081 7.731281265.34E−26 1.27E−22 216250_s_at LPXN 2.1444933 11.2374219 1.42E−253.23E−22 237252_at THBD 2.06547107 9.51011605 2.22E−25 4.86E−22235457_at MAML2 2.62488399 8.91497905 5.79E−25 1.22E−21 225171_atARHGAP18 1.83225951 10.7080346 6.66E−25 1.35E−21 204684_at NPTX12.87807656 10.9346668 1.40E−24 2.74E−21 230925_at APBB1IP 1.9428382312.7655513 2.02E−24 3.81E−21 201590_x_at ANXA2 1.68959054 13.14361753.46E−24 6.31E−21 206157_at PTX3 1.98670615 11.2102165 3.62E−24 6.38E−21216080_s_at FADS3 2.27239911 9.71739825 3.75E−24 6.39E−21 221463_atCCL24 3.58807723 8.40481021 3.93E−24 6.39E−21 210427_x_at ANXA21.67415609 13.1118777 3.98E−24 6.39E−21 213503_x_at ANXA2 1.7239935413.1135447 4.18E−24 6.51E−21 238681_at GDPD1 2.92185146 7.199015564.29E−24 6.51E−21 202458_at PRSS23 2.98100135 7.79000143 5.03E−247.43E−21 203761_at SLA 1.78030673 11.2608124 6.52E−24 9.38E−211558397_at — 2.20691751 9.17869031 8.35E−24 1.17E−20 214054_at DOK21.67191836 12.2431311 8.80E−24 1.20E−20 228937_at C13ORF31 2.428166839.90878354 9.66E−24 1.29E−20 211676_s_at IFNGR1 1.64276331 12.09958891.08E−23 1.41E−20 230966_at IL4I1 3.68319718 10.6065738 1.18E−231.50E−20 208816_x_at ANXA2P2 1.61606927 11.6007732 1.33E−23 1.66E−20204912_at IL10RA 1.88097974 10.4596073 1.53E−23 1.83E−20 220014_atLOC51334 3.95258058 6.49298277 1.54E−23 1.83E−20 218856_at TNFRSF211.97277863 11.9973199 2.06E−23 2.40E−20 34210_at CD52 1.7484162411.3194919 2.57E−23 2.92E−20 211564_s_at PDLIM4 2.13518707 9.683261052.72E−23 3.03E−20 223502_s_at TNFSF13B 1.73530598 10.5512407 2.94E−233.21E−20 202727_s_at IFNGR1 1.5463282 12.4669611 3.25E−23 3.48E−20201243_s_at ATP1B1 2.26738679 11.039008 4.33E−23 4.56E−20 209606_atPSCDBP 2.53767762 8.05776375 4.93E−23 5.08E−20 222670_s_at MAFB2.65652588 11.7521547 6.27E−23 6.35E−20 223394_at SERTAD1 1.650315249.76915308 6.91E−23 6.87E−20 214175_x_at PDLIM4 1.85137891 9.809315648.66E−23 8.45E−20 223660_at ADORA3 1.89720977 9.3830598 9.01E−238.64E−20 203217_s_at ST3GAL5 1.78903169 9.10901818 1.17E−22 1.11E−19204257_at FADS3 1.78672893 9.74459459 1.23E−22 1.14E−19 223398_atC9ORF89 1.54418891 11.0771528 1.25E−22 1.14E−19 211986_at AHNAK1.64967948 12.0209047 1.63E−22 1.45E−19 201278_at DAB2 1.568233089.36397364 1.64E−22 1.45E−19 229797_at MCOLN3 2.09980647 10.051182.01E−22 1.75E−19 202284_s_at CDKN1A 1.789083 11.1500265 2.69E−222.22E−19 228579_at — 1.73158064 8.85026747 3.40E−22 2.78E−19 204653_atTFAP2A 1.98518712 8.32878609 5.70E−22 4.39E−19 201952_at ALCAM1.52577304 12.9059918 6.14E−22 4.66E−19 202087_s_at CTSL 1.9128495311.1924209 6.47E−22 4.84E−19 208978_at CRIP2 1.99640335 10.10605686.82E−22 5.04E−19 219434_at TREM1 1.77683606 11.1148543 6.95E−225.07E−19 235911_at MFI2 1.81455526 10.1578351 7.75E−22 5.57E−19225173_at ARHGAP18 1.85956949 10.0159515 7.95E−22 5.65E−19 204661_atCD52 1.6752998 11.8608631 9.08E−22 6.28E−19 202756_s_at GPC1 1.887923838.93231998 9.08E−22 6.28E−19 227240_at NGEF 1.97393626 9.352253939.96E−22 6.66E−19 220484_at MCOLN3 2.10889009 9.93061659 9.98E−226.66E−19 214297_at CSPG4 1.98668454 8.74794884 9.99E−22 6.66E−19203355_s_at PSD3 1.68707305 9.97354098 1.13E−21 7.47E−19 212386_at —1.80977269 8.4443852 1.22E−21 7.91E−19 201242_s_at ATP1B1 2.3602056110.833866 1.62E−21 1.03E−18 203760_s_at SLA 1.76467647 10.29842961.71E−21 1.07E−18 204475_at MMP1 4.89045646 6.14908101 1.97E−21 1.21E−18228964_at PRDM1 2.42316104 9.16116313 2.05E−21 1.24E−18 205566_at ABHD21.61609464 9.56280738 2.12E−21 1.27E−18 224990_at LOC201895 1.754867179.56572435 2.15E−21 1.28E−18 214830_at SLC38A6 1.70065597 9.607776022.38E−21 1.38E−18 222876_s_at CENTA2 1.62337809 9.52111995 3.45E−211.92E−18 218501_at ARHGEF3 1.72054917 9.02047119 3.66E−21 2.02E−18206134_at ADAMDEC1 1.90734854 8.46538539 3.83E−21 2.10E−18 219385_atSLAMF8 2.3601546 8.87175449 4.64E−21 2.49E−18 212298_at NRP1 2.267061479.0154209 5.27E−21 2.77E−18 1556314_a_at — 1.94563197 9.962448845.97E−21 3.05E−18 204834_at FGL2 2.41220628 9.04212862 7.43E−21 3.63E−18227052_at — 1.7292497 9.65138189 8.49E−21 4.11E−18 223501_at —1.77755998 10.4775991 9.58E−21 4.59E−18 238669_at PTGS1 1.795269289.00713066 1.52E−20 7.11E−18 203936_s_at MMP9 1.83742157 9.542687192.01E−20 9.33E−18 205128_x_at PTGS1 1.50682893 10.8982825 2.46E−201.12E−17 223019_at C9ORF88 1.71440506 9.42451447 2.48E−20 1.12E−17218223_s_at PLEKHO1 1.76062083 9.13759715 2.55E−20 1.14E−17 226545_atCD109 2.22747108 10.1210564 2.62E−20 1.17E−17 37145_at GNLY 2.524741667.62618078 2.77E−20 1.21E−17 211661_x_at PTAFR 1.65459655 9.403486253.20E−20 1.39E−17 223434_at GBP3 1.79281477 8.94069901 5.65E−20 2.39E−17221011_s_at LBH /// LOC653743 2.14546482 7.91354368 6.67E−20 2.79E−17227478_at LOC284262 2.55523487 8.16720299 7.57E−20 3.09E−17 205933_atSETBP1 2.06852059 8.31470678 9.65E−20 3.88E−17 223126_s_at C1ORF212.0098249 9.34926366 1.00E−19 3.99E−17 214255_at ATP10A 1.874043528.48741153 1.17E−19 4.64E−17 203888_at THBD 1.74251135 12.10037681.32E−19 5.18E−17 239761_at GCNT1 1.60737016 9.89061934 1.78E−196.90E−17 205505_at GCNT1 1.68341734 9.51667582 1.80E−19 6.93E−17203665_at HMOX1 2.77855009 12.0276078 1.83E−19 7.00E−17 228490_at ABHD21.7612845 9.44137483 1.92E−19 7.27E−17 213428_s_at COL6A1 1.63658769.11385826 2.21E−19 8.27E−17 202748_at GBP2 2.05214857 8.50304242.71E−19 1.01E−16 63825_at ABHD2 1.60237791 9.12592031 3.53E−19 1.28E−16205542_at STEAP1 1.7513289 7.91561507 4.15E−19 1.49E−16 215813_s_atPTGS1 1.51668643 10.9189252 4.31E−19 1.53E−16 205891_at ADORA2B1.56662939 10.2505629 4.70E−19 1.66E−16 218613_at LOC653754 1.553981239.29556045 4.95E−19 1.73E−16 205076_s_at MTMR11 1.59326395 11.23417645.05E−19 1.76E−16 212086_at LMNA 1.50357006 12.1481348 5.14E−19 1.78E−16203104_at CSF1R 1.64383545 11.9446038 5.33E−19 1.83E−16 228368_atARHGAP20 2.23117651 8.70947261 5.37E−19 1.84E−16 227889_at AYTL11.59282395 10.8879284 5.43E−19 1.84E−16 203797_at VSNL1 1.76236329.20419419 5.45E−19 1.84E−16 210145_at PLA2G4A 1.69920287 9.861668485.50E−19 1.84E−16 220307_at CD244 1.51030196 11.2887381 6.64E−192.20E−16 201280_s_at DAB2 1.6207775 8.250618 7.03E−19 2.30E−16 205898_atCX3CR1 1.5834422 12.3392251 7.53E−19 2.45E−16 212171_x_at VEGF1.67886192 11.082533 8.08E−19 2.61E−16 205419_at EBI2 1.8796397110.3117587 8.24E−19 2.64E−16 242794_at MAML3 1.71070972 8.20000238.71E−19 2.76E−16 1553141_at C13ORF31 2.23957531 8.21534882 9.28E−192.90E−16 1556034_s_at MTMR11 1.54656669 10.734173 9.32E−19 2.90E−16202436_s_at CYP1B1 2.02651623 11.7446834 1.35E−18 4.08E−16 205718_atITGB7 1.61859456 10.0388412 1.64E−18 4.92E−16 222062_at IL27RA1.84145262 8.80213383 1.77E−18 5.26E−16 1565752_at FGD2 2.039739258.7032554 1.80E−18 5.32E−16 203140_at BCL6 1.6321005 9.84693758 1.88E−185.54E−16 209568_s_at RGL1 1.79068455 9.03375054 2.04E−18 5.92E−16212977_at CXCR7 1.95857569 9.06724806 2.73E−18 7.74E−16 225809_atDKEZP564O0823 2.61498482 6.81686881 3.21E−18 8.90E−16 223723_at MFI21.83918768 7.73004392 3.45E−18 9.49E−16 204141_at TUBB2A 1.923378747.9645182 3.55E−18 9.72E−16 219358_s_at CENTA2 1.61743685 10.36899563.67E−18 9.97E−16 218280_x_at HIST2H2AA /// LOC653610 ///H2A/R1.92645343 11.1017962 3.91E−18 1.05E−15 200884_at CKB 1.6211916810.3585418 3.91E−18 1.05E−15 213265_at PGA5 /// LOC643834 /// LOC6438471.54256466 9.03735387 4.18E−18 1.12E−15 228499_at PFKFB4 1.542654278.78361163 4.58E−18 1.22E−15 214581_x_at TNFRSF21 1.96726151 10.38624525.13E−18 1.35E−15 219256_s_at SH3TC1 1.81211933 8.14371592 5.59E−181.46E−15 227134_at SYTL1 1.63431503 10.2085878 5.74E−18 1.50E−15210512_s_at VEGF 1.61269337 12.1528461 5.88E−18 1.52E−15 220066_atCARD15 1.63208119 8.81134661 6.12E−18 1.58E−15 207610_s_at EMR21.96904599 7.45239164 6.31E−18 1.62E−15 225337_at ABHD2 1.5222630310.585684 6.47E−18 1.65E−15 1553906_s_at FGD2 1.56817402 11.67381448.15E−18 2.05E−15 210757_x_at DAB2 1.51596174 9.71603785 8.84E−182.22E−15 205306_x_at KMO 1.52538689 9.01246744 1.07E−17 2.64E−15203980_at FABP4 2.44504844 7.91709543 1.14E−17 2.81E−15 205798_at IL7R2.15224639 6.90018766 1.20E−17 2.94E−15 235299_at — 2.924554436.38887226 1.23E−17 2.99E−15 201422_at IFI30 1.53617841 12.1952 1.33E−173.23E−15 201951_at ALCAM 1.56151412 11.2835886 1.36E−17 3.29E−15219412_at RAB38 1.69022517 7.7984244 1.40E−17 3.36E−15 214290_s_atHIST2H2AA /// LOC653610 /// H2A/R 1.8793137 12.5116024 1.77E−17 4.19E−15223092_at ANKH 1.74621066 9.31182429 1.93E−17 4.53E−15 1552553_a_atCARD12 1.8300836 8.04038883 1.98E−17 4.61E−15 1565754_x_at FGD22.05302245 8.76658914 1.98E−17 4.61E−15 1562475_at DKFZP686O13271.84932663 8.38987825 2.25E−17 5.18E−15 202435_s_at CYP1B1 1.9604325211.3853309 2.26E−17 5.18E−15 222877_at NRP2 2.43002847 6.11623182.37E−17 5.41E−15 201125_s_at ITGB5 1.55447321 9.61610321 2.48E−175.62E−15 204222_s_at GLIPR1 1.64989211 10.4691144 3.30E−17 7.31E−151553142_at C13ORF31 2.72312753 7.05894587 3.42E−17 7.51E−15 201279_s_atDAB2 1.51128632 9.36621678 3.53E−17 7.64E−15 203234_at UPP1 1.743877379.56780561 3.97E−17 8.52E−15 226136_at — 1.5023264 9.021618 4.37E−179.27E−15 206206_at CD180 1.61188665 9.82309399 6.95E−17 1.43E−14212387_at — 1.62401877 7.80816226 1.05E−16 2.07E−14 204268_at S100A21.79310512 8.64238178 1.22E−16 2.38E−14 209122_at ADFP 1.6147863213.4092966 1.23E−16 2.41E−14 219994_at APBB1IP 1.87740546 9.62080941.42E−16 2.74E−14 210095_s_at IGFBP3 2.98798358 8.63072598 1.43E−162.74E−14 227948_at FGD4 1.62553487 7.73111329 1.54E−16 2.92E−14243483_at TRPM8 2.13837999 7.16652124 1.62E−16 3.04E−14 212062_at ATP9A2.12888023 7.50745486 1.77E−16 3.29E−14 218502_s_at TRPS1 1.613876718.89822927 1.95E−16 3.60E−14 213891_s_at — 1.67207935 8.309170842.03E−16 3.68E−14 200878_at EPAS1 1.51714595 9.20362299 2.04E−163.69E−14 201565_s_at ID2 1.52829092 12.7810873 2.26E−16 4.06E−14212190_at SERPINE2 1.92452066 9.90116936 2.57E−16 4.60E−14 224480_s_atLPAAT-THETA 1.96245654 8.74709429 2.64E−16 4.67E−14 220333_at PAQR53.58344803 7.84174393 2.70E−16 4.76E−14 218589_at P2RY5 1.651497959.3651465 3.00E−16 5.23E−14 225166_at ARHGAP18 1.75622288 7.333981363.29E−16 5.64E−14 226066_at MITF 1.750697 7.87439597 3.35E−16 5.73E−14221211_s_at C21ORF7 2.08949444 5.978895 3.41E−16 5.80E−14 225842_atPHLDA1 2.51724542 8.55236084 3.48E−16 5.89E−14 1554992_at RASGRF11.56735654 6.94135257 3.77E−16 6.35E−14 225097_at HIPK2 1.5075398610.7130384 3.84E−16 6.45E−14 212464_s_at FN1 1.70809888 9.264848124.53E−16 7.53E−14 240076_at — 1.5987436 8.40204375 4.66E−16 7.73E−14203798_s_at VSNL1 1.91644457 7.87623269 4.84E−16 7.92E−14 204575_s_atMMP19 /// LOC652543 1.83367508 7.70439226 4.88E−16 7.96E−14 204465_s_atINA 1.60147629 8.20221976 5.17E−16 8.36E−14 201566_x_at ID2 /// ID281.57371123 10.7833858 5.52E−16 8.87E−14 230360_at GLDN 1.980869596.74193069 6.80E−16 1.07E−13 222146_s_at TCF4 1.54556332 7.514723518.25E−16 1.28E−13 224341_x_at TLR4 1.7396424 8.97197657 8.61E−161.32E−13 219637_at ARMC9 1.80286893 7.06720581 8.87E−16 1.35E−13211138_s_at KMO 1.54711526 8.79132849 9.12E−16 1.38E−13 202437_s_atCYP1B1 1.80921395 12.1893518 9.54E−16 1.43E−13 235458_at HAVCR22.48536941 7.7122454 9.75E−16 1.46E−13 203922_s_at CYBB 1.5844981510.3814577 1.07E−15 1.58E−13 212143_s_at IGFBP3 2.76854721 7.929683751.26E−15 1.82E−13 227716_at UBXD5 1.51942114 9.002862 1.28E−15 1.83E−13214211_at FTH1 1.55999567 12.4970466 1.33E−15 1.90E−13 229004_at —1.51039984 9.12368109 1.55E−15 2.18E−13 202609_at EPS8 1.59240978.52061192 1.82E−15 2.52E−13 217757_at A2M 1.67532065 8.4520092 1.98E−152.73E−13 1552798_a_at TLR4 1.62695353 9.04302518 2.09E−15 2.88E−1357715_at FAM26B 1.79873285 7.75582627 2.40E−15 3.27E−13 226282_at —1.60485814 9.41013847 2.84E−15 3.80E−13 222838_at SLAMF7 1.861218447.05728625 3.11E−15 4.13E−13 216442_x_at FN1 1.69780521 10.14093613.73E−15 4.87E−13 201324_at EMP1 2.82050293 6.11305975 3.81E−15 4.94E−13210264_at GPR35 1.59109619 9.60072153 3.91E−15 5.05E−13 222858_s_atDAPP1 1.6313133 10.6750257 4.54E−15 5.78E−13 209684_at RIN2 2.162885637.25953396 5.48E−15 6.84E−13 201069_at MMP2 1.51386957 8.698555326.09E−15 7.55E−13 204998_s_at ATF5 1.63500149 10.6267979 6.14E−157.60E−13 202434_s_at CYP1B1 2.2027314 9.83119314 6.94E−15 8.52E−13205099_s_at CCR1 1.57264838 9.76018397 7.25E−15 8.85E−13 207233_s_atMITF 1.66865012 8.30250431 8.03E−15 9.72E−13 205552_s_at OAS1 1.794525327.29881386 8.53E−15 1.02E−12 226550_at — 1.79237731 7.77105086 9.20E−151.09E−12 212090_s_at MTUS1 1.62315248 8.50418445 9.61E−15 1.13E−12222651_s_at TRPS1 1.5940306 10.0878238 9.64E−15 1.13E−12 211719_x_at FN11.74293625 10.1007312 9.80E−15 1.15E−12 227609_at EPSTI1 1.735313727.62913716 1.06E−14 1.24E−12 1558105_a_at — 1.89855059 6.810461821.07E−14 1.25E−12 225207_at PDK4 2.24881528 8.76581849 1.08E−14 1.25E−12237160_at CCDC83 2.26816884 5.8347316 1.15E−14 1.33E−12 211026_s_at MGLL1.80987658 8.99536888 1.33E−14 1.53E−12 229450_at — 2.079796836.90012377 1.42E−14 1.62E−12 215602_at FGD2 2.01984347 7.859839351.54E−14 1.74E−12 228708_at RAB27B 1.75996236 8.57073526 1.63E−141.83E−12 210258_at RGS13 2.4181722 5.06675503 1.77E−14 1.97E−12210895_s_at CD86 1.74036933 7.80363779 1.88E−14 2.07E−12 223672_at SGIP11.58033388 8.69396513 1.96E−14 2.14E−12 210513_s_at VEGF 1.629607529.66705476 2.08E−14 2.25E−12 212614_at ARID5B 1.64330835 6.345921712.09E−14 2.26E−12 1553995_a_at NT5E 2.06345466 6.49987213 2.17E−142.32E−12 233540_s_at CDK5RAP2 1.77928193 10.6899414 2.34E−14 2.48E−12204059_s_at ME1 1.78078662 11.5066468 2.46E−14 2.58E−12 211527_x_at VEGF1.68079685 9.90807927 2.48E−14 2.60E−12 214724_at DIXDC1 1.558920617.67060007 2.63E−14 2.74E−12 227556_at NME7 2.07486651 9.318511292.92E−14 3.02E−12 237442_at APBB1IP 1.97657406 7.17373032 3.09E−143.18E−12 224218_s_at TRPS1 1.52587932 8.16882094 3.38E−14 3.46E−12225188_at RAPH1 1.90298066 6.31647018 3.68E−14 3.73E−12 244414_at MAML22.39160043 8.05798482 3.70E−14 3.74E−12 209906_at C3AR1 1.620349688.32122922 3.73E−14 3.76E−12 210510_s_at NRP1 1.56055098 7.31714343.77E−14 3.78E−12 226629_at SLC43A2 1.57641868 8.50211433 3.97E−143.94E−12 237030_at ACPP 1.53890938 8.05225501 4.15E−14 4.10E−12213338_at TMEM158 1.73773739 10.7585184 4.18E−14 4.13E−12 219926_atPOPDC3 2.12181972 6.63647483 5.99E−14 5.68E−12 200897_s_at PALLD1.64882729 8.35346573 6.07E−14 5.74E−12 208436_s_at IRF7 1.550758858.74418094 6.34E−14 5.96E−12 228438_at TRPA1 1.65933581 10.39501676.81E−14 6.30E−12 227747_at — 1.55198677 7.93194342 6.84E−14 6.32E−121554867_a_at LOC51334 1.86507425 7.40812044 6.90E−14 6.36E−121563445_x_at CTSLL3 1.82851184 6.84405898 9.09E−14 8.12E−12 242903_atIFNGR1 1.7678462 7.97757472 9.49E−14 8.42E−12 229900_at CD109 1.540892888.62103824 1.05E−13 9.24E−12 210495_x_at FN1 1.61505134 10.09739351.07E−13 9.43E−12 218854_at SART2 1.54263807 8.36626559 1.13E−139.81E−12 224989_at — 1.78010467 7.75893731 1.17E−13 1.02E−11 238638_atSLC37A2 1.63842433 9.93438242 1.31E−13 1.13E−11 212382_at — 1.605058347.06996616 1.35E−13 1.15E−11 209047_at AQP1 2.44653569 7.847208271.38E−13 1.17E−11 236345_at TBXAS1 1.66860916 8.46774141 1.40E−131.18E−11 228873_at COL22A1 1.56093003 7.43196243 1.41E−13 1.19E−11239519_at NRP1 2.19110297 5.55763801 1.43E−13 1.20E−11 220935_s_atCDK5RAP2 1.84541222 10.4100106 1.54E−13 1.28E−11 1560228_at SNAI31.91948596 7.8146015 1.56E−13 1.30E−11 218934_s_at HSPB7 1.650405268.10534113 2.40E−13 1.90E−11 210146_x_at LILRB2 1.9982938 6.764237662.86E−13 2.22E−11 209348_s_at MAF 1.56472875 8.72338323 3.17E−132.42E−11 1558569_at LOC645238 1.75050375 7.56283286 3.25E−13 2.47E−11243856_at — 1.73115631 8.03640769 3.81E−13 2.86E−11 223798_at SLC41A21.94681117 6.54582797 3.90E−13 2.92E−11 215990_s_at BCL6 1.506719438.04953142 4.81E−13 3.52E−11 202869_at OAS1 1.63942747 6.735200185.30E−13 3.86E−11 225631_at KIAA1706 1.53753899 7.78142994 5.56E−134.03E−11 204116_at IL2RG 1.53970115 7.99806857 5.88E−13 4.22E−11225189_s_at RAPH1 1.85367315 6.14549622 6.27E−13 4.47E−11 211066_x_atPCDHGC3 /// PCDHGB4 /// PCDHGA8 1.58678656 10.4111947 7.90E−13 5.53E−11/// PCDHGA12 /// PCDHGC5 /// PCDHGC4 /// PCDHGB7 /// PCDHGB6 /// PCDHGB5/// PCDHGB3 /// PCDHGB2 /// PCDHGB1 /// PCDHGA11 /// PCDHGA10 ///PCDHGA9 /// PCDHGA7 /// PCDHGA6 /// PCDHGA5 /// PCDHGA4 /// PCDHGA3 ///PCDHGA2 /// PCDHGA1 221266_s_at TM7SF4 1.83671444 6.22762311 8.02E−135.60E−11 1560485_at HIVEP1 1.6480621 6.99003908 8.06E−13 5.62E−11204881_s_at UGCG 1.5102382 9.51481557 8.38E−13 5.83E−11 235286_at CKLF1.61741462 8.34288205 9.26E−13 6.36E−11 205003_at DOCK4 1.51126898.20388936 1.02E−12 6.92E−11 218686_s_at RHBDF1 1.51723286 7.924822721.05E−12 7.08E−11 221565_s_at FAM26B 1.59642371 7.91366407 1.09E−127.32E−11 206675_s_at SKIL 1.61042514 7.42083013 1.16E−12 7.69E−11242358_at — 2.20249712 6.04968315 1.24E−12 8.20E−11 241392_at TMEM39A1.61384348 7.05009494 1.87E−12 1.19E−10 232333_at MAML2 1.684811568.01950459 2.06E−12 1.30E−10 228762_at LFNG 1.55190457 9.04030742.08E−12 1.31E−10 242907_at GBP2 2.14738965 6.03707956 2.72E−12 1.64E−10203753_at TCF4 1.50293289 7.66442858 2.78E−12 1.68E−10 207542_s_at AQP11.69421791 6.82177348 3.02E−12 1.81E−10 242157_at — 1.573830988.76647265 3.26E−12 1.94E−10 204058_at ME1 1.73420796 9.515082633.53E−12 2.08E−10 209921_at SLC7A11 1.94348494 9.29226579 3.63E−122.13E−10 211030_s_at SLC6A6 1.51035569 7.57360907 3.78E−12 2.21E−10209392_at ENPP2 1.82310668 5.23034508 4.76E−12 2.73E−10 243894_atSLC41A2 1.69547735 5.15085274 4.80E−12 2.75E−10 229937_x_at LILRB11.58545389 7.41501062 5.00E−12 2.84E−10 214857_at C10ORF95 1.602553687.13065345 5.02E−12 2.85E−10 230944_at MGC45491 1.55203348 7.478873625.53E−12 3.14E−10 228057_at DDIT4L 1.68290143 9.61033195 6.99E−123.82E−10 204105_s_at NRCAM 2.27634648 6.95288228 7.49E−12 4.07E−10205681_at BCL2A1 1.64702983 9.50173198 8.19E−12 4.40E−10 242405_at MAML21.86052011 7.15057318 1.10E−11 5.73E−10 217678_at SLC7A11 1.759135558.8692241 1.22E−11 6.25E−10 211962_s_at ZFP36L1 1.59912563 8.82322051.23E−11 6.27E−10 221060_s_at TLR4 1.53812487 8.81340284 2.27E−111.08E−09 200907_s_at PALLD 1.50739688 7.44132987 2.28E−11 1.08E−09228918_at SLC43A2 1.66364865 7.20166079 2.29E−11 1.09E−09 1555606_a_atGDPD1 1.51121338 6.61034166 2.39E−11 1.13E−09 228450_at PLEKHA71.50941089 6.45253703 2.70E−11 1.26E−09 229221_at — 1.602635928.59003199 4.03E−11 1.79E−09 229635_at LOC643424 1.53074512 7.552151784.38E−11 1.94E−09 1569149_at PDLIM7 1.54849621 9.14969141 5.56E−112.41E−09 207433_at IL10 1.52400243 5.63708634 7.49E−11 3.14E−09221815_at ABHD2 1.55904737 8.11542769 1.01E−10 4.08E−09 203060_s_atPAPSS2 1.5764103 7.75963014 1.25E−10 4.94E−09 232746_at CXCR7 2.07198936.54641126 1.43E−10 5.55E−09 1560960_at MDGA1 1.97885133 5.715415241.47E−10 5.70E−09 234645_at MAML2 1.87005824 6.53786268 1.72E−106.50E−09 223596_at SLC12A6 1.50709112 7.32492551 1.75E−10 6.60E−0987100_at ABHD2 1.51939681 7.38326685 1.79E−10 6.75E−09 213931_at ID2 ///ID2B 2.71874933 9.84931953 1.87E−10 7.02E−09 216874_at DKFZP686O13271.70886875 5.93467446 2.11E−10 7.76E−09 244375_at EVL 1.565237727.93537524 2.24E−10 8.16E−09 1569150_x_at PDLIM7 1.54117409 9.379433592.24E−10 8.18E−09 214453_s_at IFI44 1.79674041 6.65852583 2.78E−109.87E−09 204999_s_at ATF5 1.64452594 9.14215678 3.41E−10 1.18E−08215836_s_at PCDHGC3 /// PCDHGB4 /// PCDHGA8 1.52441384 9.290791224.72E−10 1.60E−08 /// PCDHGA12 /// PCDHGC5 /// PCDHGC4 /// PCDHGB7 ///PCDHGB6 /// PCDHGB5 /// PCDHGB3 /// PCDHGB2 /// PCDHGB1 /// PCDHGA11 ///PCDHGA10 /// PCDHGA9 /// PCDHGA7 /// PCDHGA6 /// PCDHGA5 /// PCDHGA4 ///PCDHGA3 /// PCDHGA2 /// PCDHGA1 208161_s_at ABCC3 1.61726316 8.401898685.05E−10 1.69E−08 202827_s_at MMP14 1.62314882 10.2030389 5.39E−101.78E−08 208712_at CCND1 1.5393933 7.40438263 6.16E−10 2.01E−08223939_at SUCNR1 1.57537424 8.40597144 7.17E−10 2.32E−08 205960_at PDK41.69465703 7.19094792 1.28E−09 3.84E−08 214841_at CNIH3 1.562533176.14111085 1.40E−09 4.15E−08 209993_at ABCB1 1.58407983 5.068806431.52E−09 4.48E−08 1557938_s_at PTRF 1.50339198 6.8700736 1.62E−094.73E−08 232068_s_at TLR4 1.74396268 6.76798691 1.84E−09 5.28E−08242321_at — 1.6662739 6.52856887 2.12E−09 5.99E−08 219574_at MARCH11.64000788 5.55000344 3.54E−09 9.43E−08 202638_s_at ICAM1 1.587532946.72394157 3.76E−09 9.97E−08 219496_at ANKRD57 1.50970429 7.475837444.86E−09 1.26E−07 1555756_a_at CLEC7A 1.65932872 7.0882743 5.25E−091.35E−07 241929_at CD36 1.82152709 8.32014251 5.66E−09 1.44E−071556423_at VASH1 1.55220936 7.02874938 8.01E−09 1.97E−07 229435_at GLIS31.5824943 4.92660385 8.07E−09 1.98E−07 217997_at PHLDA1 2.018712087.37991533 8.18E−09 2.00E−07 235944_at HMCN1 1.51434592 7.3316819.15E−09 2.21E−07 206637_at P2RY14 1.69022854 4.58701985 9.57E−092.30E−07 213293_s_at TRiM22 1.54165851 6.59931282 9.57E−09 2.30E−07238581_at GBP5 1.57383447 7.67594481 1.03E−08 2.46E−07 1558404_atLOC644242 /// LOC650429 /// 1.85121181 5.31545142 1.46E−08 3.35E−07LOC650446 230559_x_at FGD4 1.51987215 5.45151267 1.69E−08 3.83E−071553151_at ATP6V0D2 1.52950999 6.78084809 1.69E−08 3.84E−07 1554285_atHAVCR2 1.64907555 7.49492704 3.00E−08 6.38E−07 244579_at TRPS1 1.53542618.45494277 5.93E−08 1.16E−06 228640_at — 1.5809974 4.58101232 7.52E−081.43E−06 210004_at OLR1 1.59400178 5.26939608 8.40E−08 1.58E−06243556_at NGEF 1.50840974 6.73352627 1.18E−07 2.14E−06 210360_s_at MTSS11.7452905 6.18923946 1.40E−07 2.49E−06 217999_s_at PHLDA1 1.733106686.08679858 2.07E−07 3.52E−06 227062_at TNCRNA 1.56840333 10.04415712.18E−07 3.69E−06 237904_at ADORA3 1.52521897 6.15098521 2.49E−074.15E−06 1563621_at KIAA1706 1.55572929 7.60284745 6.48E−07 9.74E−06Down regulated: 207725_at POU4F2 −2.8001105 9.19852692 2.12E−22 1.81E−19212993_at — −1.8809512 9.86599984 2.25E−22 1.89E−19 211421_s_at RET−2.0125505 9.36968529 3.53E−22 2.84E−19 227899_at VIT −1.87543227.70929876 4.25E−22 3.36E−19 225224_at C20ORF112 −2.04379 8.59647851.37E−21 8.79E−19 213361_at TDRD7 −1.8488643 10.2732718 2.93E−211.67E−18 214539_at SERPINB10 −2.1313083 8.01802953 3.16E−21 1.78E−18235275_at OXCT2 −2.0229254 12.4009174 4.06E−21 2.20E−18 203685_at BCL2−2.3112793 8.44431889 4.88E−21 2.59E−18 227037_at LOC201164 −1.54684429.38990462 5.65E−21 2.94E−18 219714_s_at CACNA2D3 −2.206206 9.827244285.72E−21 2.95E−18 206643_at HAL −1.9307917 9.28853464 6.18E−21 3.10E−18211144_x_at TRGC2 /// TRGV2 /// TRGV9 /// TARP −1.5748474 10.5868187.12E−21 3.54E−18 /// LOC642083 217521_at — −1.7887534 8.383802637.38E−21 3.63E−18 208206_s_at RASGRP2 −1.9706562 9.9264082 1.25E−205.95E−18 228977_at IL17D −2.1132305 7.51309566 2.19E−20 1.01E−17209813_x_at TRGC2 /// TRGV2 /// TRGV9 /// TARP −1.6036338 10.76974753.87E−20 1.65E−17 /// LOC642083 204614_at SERPINB2 −2.3610663 10.83530356.10E−20 2.57E−17 212110_at SLC39A14 −1.682778 10.5673949 7.23E−203.00E−17 202444_s_at SPFH1 −1.8415073 9.34800962 7.37E−20 3.03E−17216920_s_at TRGC2 /// TRGV2 /// TRGV9 /// TARP −1.5704575 11.34919578.78E−20 3.56E−17 /// LOC642083 202441_at SPFH1 −1.6532676 11.14118921.45E−19 5.66E−17 211919_s_at CXCR4 −1.5387599 11.0738986 3.40E−191.25E−16 204610_s_at CCDC85B −1.729942 9.65009386 6.61E−19 2.20E−16200999_s_at CKAP4 −1.6192589 11.5934013 8.23E−19 2.64E−16 207865_s_atBMP8B −2.145585 9.11410521 9.38E−19 2.90E−16 217028_at CXCR4 −1.527442811.5438714 1.14E−18 3.50E−16 201968_s_at PGM1 −1.5051483 9.065463682.12E−18 6.10E−16 219463_at C20ORF103 −1.5731957 10.0186106 2.55E−187.26E−16 212242_at TUBA1 −1.5626324 11.2879097 2.82E−18 7.96E−16213484_at — −1.5736546 8.53538561 3.16E−18 8.83E−16 209201_x_at CXCR4−1.5448129 11.1194624 3.16E−18 8.83E−16 218858_at DEPDC6 −1.78669197.55045943 5.06E−18 1.34E−15 202236_s_at SLC16A1 −1.5384699 10.16757399.26E−18 2.30E−15 208158_s_at OSBPL1A −1.6142678 8.3746552 1.71E−174.06E−15 202932_at YES1 −1.6455703 8.57014581 2.47E−17 5.62E−15243209_at KCNQ4 −2.2463943 6.9665965 2.56E−17 5.79E−15 215806_x_at TRGC2/// TRGV2 /// TRGV9 /// TARP −1.5328764 11.0634752 3.51E−17 7.61E−15 ///LOC642083 204521_at C12ORF24 −1.5676281 10.1844282 3.88E−17 8.36E−15204301_at KBTBD11 −1.5574513 10.253905 4.37E−17 9.27E−15 227920_atKIAA1553 −1.6307063 8.01525239 5.17E−17 1.09E−14 218251_at MID1IP1−1.559714 9.78570246 5.29E−17 1.11E−14 212646_at RFTN1 −1.6583158.57843565 5.38E−17 1.12E−14 222799_at HSPC049 −1.5489442 8.600856281.10E−16 2.17E−14 227103_s_at MGC2408 −1.581709 8.7267591 1.30E−162.51E−14 206067_s_at WT1 −1.511783 9.85618462 1.37E−16 2.66E−14214369_s_at RASGRP2 −1.5808582 9.41805033 1.69E−16 3.15E−14 206589_atGFI1 −1.5996464 11.7281473 1.99E−16 3.65E−14 225619_at SLAIN1 −2.24538897.41012008 2.01E−16 3.68E−14 212660_at PHF15 −1.69531 8.007528752.63E−16 4.66E−14 218971_s_at HSPC049 −1.5087203 9.12721477 3.08E−165.33E−14 201690_s_at TPD52 −1.5492402 9.27038373 3.25E−16 5.59E−14229638_at IRX3 −1.6570492 11.8844594 3.38E−16 5.76E−14 223062_s_at PSAT1−1.556602 9.43823571 4.70E−16 7.77E−14 225510_at OAF −1.663272710.1142626 6.67E−16 1.05E−13 209485_s_at OSBPL1A −1.6049308 8.369109297.34E−16 1.15E−13 204432_at SOX12 −1.7584476 6.5781916 8.71E−16 1.33E−13205768_s_at SLC27A2 −1.6303006 7.69181894 8.98E−16 1.36E−13 211576_s_atSLC19A1 −1.5339487 9.8247482 9.81E−16 1.46E−13 201688_s_at TPD52−1.6048433 8.65393713 9.93E−16 1.48E−13 50314_i_at C20ORF27 −1.5611729.67877203 1.14E−15 1.66E−13 1553436_at MUC19 −1.64037 7.997177261.18E−15 1.71E−13 202800_at SLC1A3 −1.5176496 8.18097955 1.51E−152.13E−13 41037_at TEAD4 −1.6405647 6.31029525 1.70E−15 2.36E−13216953_s_at WT1 −1.5276508 7.76890727 2.15E−15 2.95E−13 228055_at NAPSB−1.5385754 10.1648177 2.61E−15 3.52E−13 218424_s_at STEAP3 −1.76928827.88028032 2.78E−15 3.74E−13 212855_at DCUN1D4 −1.508562 7.888878612.92E−15 3.90E−13 202933_s_at YES1 −1.5437793 9.12374841 3.76E−154.89E−13 1553138_a_at ANKRD41 −2.0146608 6.96935627 6.26E−15 7.73E−13227242_s_at EBF3 −1.8363477 4.86769268 8.15E−15 9.84E−13 237265_atC16ORF73 −1.5296704 9.74165113 9.60E−15 1.13E−12 213478_at KIAA1026−1.8330762 7.39399329 1.16E−14 1.34E−12 225081_s_at CDCA7L −1.549172710.2951966 1.46E−14 1.66E−12 211299_s_at FLOT2 −1.6145204 9.108641731.58E−14 1.79E−12 213568_at OSR2 −2.2462672 5.99962469 1.64E−14 1.83E−12227662_at SYNPO2 −1.5973696 8.62811124 1.76E−14 1.96E−12 200998_s_atCKAP4 −1.6910951 9.77491302 2.08E−14 2.25E−12 209900_s_at SLC16A1−1.5885969 7.84437981 2.30E−14 2.43E−12 229084_at CNTN4 −1.64151367.72735571 2.30E−14 2.43E−12 238694_at — −1.5762461 7.26420148 3.38E−143.46E−12 1555788_a_at TRIB3 −1.5022329 9.92495817 3.64E−14 3.70E−12221900_at COL8A2 −1.5627579 10.2358313 4.09E−14 4.05E−12 225016_atAPCDD1 −1.6872345 6.47036912 4.21E−14 4.14E−12 225768_at NR1D2−1.7351352 6.8044854 5.44E−14 5.24E−12 222095_s_at C1ORF76 −1.73019567.38672115 6.40E−14 6.00E−12 229103_at WNT3 −1.7749895 5.555037827.97E−14 7.21E−12 205769_at SLC27A2 −1.7824201 7.67753108 1.53E−131.27E−11 201689_s_at TPD52 −1.645479 8.12663653 1.59E−13 1.31E−11201350_at FLOT2 −1.5079906 11.0344892 2.08E−13 1.68E−11 221648_s_atC1ORF121 −1.517313 8.36815023 2.55E−13 2.00E−11 208078_s_at SNF1LK−1.597736 7.64505173 2.81E−13 2.18E−11 1562484_at FLJ35848 −1.90502096.65405977 3.15E−13 2.41E−11 1555370_a_at CAMTA1 −1.7040191 6.360417573.26E−13 2.47E−11 218376_s_at MICAL1 −1.5055354 11.194367 3.44E−132.61E−11 204567_s_at ABCG1 −1.8330717 5.8226155 3.51E−13 2.66E−1139966_at CSPG5 −1.6105172 7.68266153 4.12E−13 3.07E−11 218326_s_at LGR4−1.696564 6.525917 5.28E−13 3.85E−11 212430_at RBM38 −1.58841378.88476901 5.78E−13 4.17E−11 227236_at TSPAN2 −1.7695047 6.984341197.37E−13 5.19E−11 204794_at DUSP2 −1.5957268 8.45706393 7.96E−135.57E−11 230888_at HSPC049 −1.577802 7.20584208 9.14E−13 6.29E−11212097_at CAV1 −1.6628831 7.59130877 9.63E−13 6.57E−11 209353_s_atC1ORF76 −1.7131519 7.30778535 1.02E−12 6.92E−11 201801_s_at SLC29A1−1.6246978 8.73200853 1.05E−12 7.08E−11 210279_at GPR18 −1.53503158.98079125 1.29E−12 8.49E−11 52651_at COL8A2 −1.577706 9.95166371.31E−12 8.57E−11 235758_at PNMA6A −1.5784572 7.86091427 1.34E−128.77E−11 222162_s_at ADAMTS1 −1.842254 6.45805339 1.37E−12 8.95E−11209369_at ANXA3 −1.7449323 5.34631362 1.41E−12 9.18E−11 219911_s_atSLCO4A1 −1.5143987 8.17455361 1.50E−12 9.71E−11 1557919_a_at LOC648232−1.5028156 12.5466889 1.73E−12 1.11E−10 219497_s_at BCL11A −1.58258539.14635109 1.85E−12 1.18E−10 232271_at HNF4G −1.5978388 7.37152252.04E−12 1.29E−10 206653_at — −1.5611734 6.70426513 2.13E−12 1.33E−10225782_at MSRB3 −1.5020089 8.17316381 2.54E−12 1.55E−10 223704_s_atDMRT2 −1.6370445 6.61601092 5.67E−12 3.20E−10 1558613_at OAF −1.57765357.5183993 6.15E−12 3.44E−10 1555434_a_at SLC39A14 −1.5483414 7.913889696.58E−12 3.65E−10 1556194_a_at — −1.7264827 7.80933003 1.10E−11 5.73E−10219304_s_at PDGFD −1.5313053 8.14849618 1.10E−11 5.73E−10 200894_s_atFKBP4 −1.6280907 8.06454238 1.28E−11 6.49E−10 210347_s_at BCL11A−1.5419287 7.82101671 1.36E−11 6.85E−10 221249_s_at FAM117A −1.59201488.42643515 1.45E−11 7.21E−10 239410_at — −1.521547 6.86497836 1.72E−118.46E−10 206039_at RAB33A −1.5487461 8.85562976 2.20E−11 1.05E−091554660_a_at C1ORF71 −1.5203911 7.61313106 2.54E−11 1.19E−09 209776_s_atSLC19A1 −1.5451778 7.72495148 2.90E−11 1.34E−09 1560495_at — −1.64784097.28259363 3.01E−11 1.386−09 202234_s_at SLC16A1 −1.5891823 7.762407854.97E−11 2.16E−09 207768_at EGR4 −2.266679 5.08097601 7.18E−11 3.02E−09207717_s_at PKP2 −1.5155863 4.5970225 1.26E−10 4.97E−09 213912_atKIAA0984 −1.5617265 6.49154577 1.30E−10 5.13E−09 222891_s_at BCL11A−1.5929549 8.42933212 2.00E−10 7.44E−09 213268_at CAMTA1 −1.74609735.75010725 2.03E−10 7.52E−09 232007_at — −1.5199738 9.70608088 2.60E−109.33E−09 227099_s_at LOC387763 −1.5087957 6.4279952 2.97E−10 1.05E−08232614_at BCL2 −1.6221488 7.30276639 2.99E−10 1.05E−08 222668_at KCTD15−1.5400712 5.79509816 3.31E−10 1.15E−08 213610_s_at KLHL23 −1.57309887.2326013 4.60E−10 1.56E−08 206935_at PCDH8 −1.6992238 5.663803116.65E−10 2.16E−08 203708_at PDE4B −1.5144333 7.44164625 8.10E−102.59E−08 1554298_a_at WDR49 −1.5642625 6.77053726 8.63E−10 2.73E−08212558_at SPRY1 −1.6087624 5.95823849 1.41E−09 4.18E−08 242509_atC16ORF74 −1.5318238 6.48465026 2.21E−09 6.20E−08 201939_at PLK2−1.5317787 7.43694803 5.43E−09 1.39E−07 242245_at SYDE2 −1.58514544.93022084 5.57E−09 1.42E−07 204557_s_at DZIP1 −1.5326546 5.012170495.85E−09 1.48E−07 204875_s_at GMDS −1.7607496 6.33236847 9.81E−092.35E−07 204285_s_at PMAIP1 −1.7424137 10.9563243 1.15E−08 2.73E−07213006_at CEBPD −1.9902998 8.08295825 1.47E−08 3.38E−07 1554830_a_atSTEAP3 −1.6156641 5.65856155 2.19E−08 4.84E−07 204286_s_at PMAIP1−1.7353429 9.45448346 6.05E−08 1.18E−06 228325_at KIAA0146 −1.88196768.36526925 8.31E−08 1.57E−06 1569377_at TMEM67 −1.9524092 4.48882771.11E−07 2.04E−06 242892_at PER2 −2.1304461 6.97699912 1.72E−07 3.00E−061555847_a_at LOC84454 −2.1798122 9.88866319 1.88E−07 3.24E−06

Discussion Example 1

The significant gene-expression changes observed in the human THP-1 cellline due to treatment with branded GA included changes consistent withprevious literature (as discussed below), supporting the validity of thechosen model system and current study design for revealing relevanttreatment effects.

For example, expression of the anti-inflammatory gene IL10 was increasedat the 6 hour timepoint, consistent with known GA mechanism with regardto monocytes (Kim et al. J. Immunol. Baltim. Md 1950, 2004; Weber et al.Nat. Med. 2007; Mahad et al. Brain J. Neurol. 2006). GA is thought toinduce an anti-inflammatory effect, mediated by secretion of IL-4,IL-10, and other anti inflammatory cytokines both in terms of T cells(Th1 to Th2 shift) but also in terms of monocytes, resulting in a shiftfrom monocyte production of IL-12 to anti-inflammatory IL-10. Forexample, monocytes from mice treated with GA secreted more IL-10 thanmonocytes from untreated mice (Weber, Nat Med 2007), and monocytesisolated from MS patients treated with GA were shown to produce moreIL-10 relative to untreated patients (Kim, J Immunol 2004). In addition,dendritic cells exposed to GA during maturation increased theirproduction of IL-10 (Mahad et al. Brain J. Neurol. 2006).

Another anti-inflammatory gene, IL1RN (encoding IL-1ra, a protein thatinhibits the activities of IL-1a and IL-1b) showed increased expressionat all three timepoints. These observations are consistent with workshowing that blood levels of soluble IL1-ra increase with GA treatmentin patients with MS as well as EAE mice, and that soluble IL1-ra isupregulated by GA treatment in human monocytes either stimulated withLPS or activated by T cell contact (Burger et al, PNAS 2009).

Branded GA significantly modulated many pathways (Table 5). At 6h,pathways enriched significantly among upregulated genes included broadcategories such as immune response and regulation of immune processes,and more specifically cytokine-cytokine receptor interactions. Othersignificantly enriched pathways included adhesion, and other pathwayswith broad relevance to the disease process and/or proposed action ofGA. Several of these pathways were also significantly enriched amonggenes modulated by GA in monocytes from RRMS patients (Rosenberg, TheLancet 2005).

Example 2 Differences in Gene Expression Induced by Probioglat VersusBranded GA

To identify differences between branded GA and differently manufacturedglatiramoids, differential gene expression analysis was performed tocompare directly between profiles induced by branded GA and by thepurported generic glatiramoid, Probioglat. The standard R LIMMAbioconductor package was utilized to measure differentially expressedprobesets across the entire microarray. To compare GA and Probioglat,comparisons were corrected to compare each treatment relative tomannitol control (i.e., [GA vs mannitol] was compared via LIMMA to[Probioglat vs mannitol]). Probesets were filtered by calls of presenceon the chip for the relevant samples in the comparison (to be consideredpresent at a given timepoint, a probeset was required to have on averagea call of present or marginal across the relevant samples at thattimepoint). Probesets were mapped to genes using the annotationavailable for the U133 Plus 2.0 chip from Affymetrix. FDR adjusted pvalues reported for genes represent the lowest FDR adjusted p value forpresent probesets for that gene.

Many significant differences were observed between GA and Probioiglat(Table 3). As expected based on the more extensive response to GA at 6h,the most differences were observed at the 6h timepoint.

TABLE 3 Dynamic profiles of differentially expressed RNA afterstimulation of THP-1 cells by Probioglat versus Copaxone ® Stimulationtime 6 hours 12 hours 24 hours Significance Genes Probesets GenesProbesets Genes Probesets threshold # # # # # # Upregulated: FDR- 115138 5 5 1 1 adjusted p (MMP9) value < 0.05 Nominal 2,597 3,310 1,2961,560 1,625 1,959 p value < 0.05 Total FDR- 136 162 7 7 1 1 modulatedadjusted p (MMP9) (up- and value < 0.05 down- Nominal 4,863 6,208 3,0513,992 2,843 3,486 regulated): p value < 0.05 Numbers of genes andprobesets modulated by Probioglat relative to GA(percent of probesets detected as significantly differentiated betweentreatments as percentage of the total 47,000 probesets included in theAffymetrix U133 Plus 2.0 chip)

See Table 4a for the full list of differentially-expressed probesets at6h: 138 upregulated, 24 downregulated (126 upregulated, 22 downregulatedafter presence/absence filtering). These differences includedproinflammatory genes that were increased in expression by Probioglatrelative to GA, including CCL5, CCL2, MMP9, MMP1, CXCL10, CD14, ICAM1and BIRC3 (all significant by FDR adjusted p value<0.05) (Table 4a). Atthe same time, differences were observed in levels of anti-inflammatorygenes. Probioglat downregulated anti-inflammatory genes CISH and HSPD1relative to GA, and upregulated IL10 and PRDM1 relative to branded GA(all significant by FDR adjusted p value<0.05).

TABLE 4a Human monocyte study: probesets significantly modulated byCopaxone ® relative to Probioglat Comparing GA to Probioglat(mannitol-corrected): Gene ID raw. FC AveExpr t P. Value adj. P. Val BUpregulated: 6 hr: MMP9 203936_s_at −1.2926295 9.63366142 −9.00417915.02E−11 2.74E−06 13.793663 CXCL10 204533_at −1.4567769 5.93611913−6.8101441 4.11E−08 0.00056208 8.11662055 PRDM1 228964_at −1.31315439.26923221 −6.9712916 2.48E−08 0.00056208 8.55501455 LPXN 216250_s_at−1.1874257 11.315416 −6.8905168 3.19E−08 0.00056208 8.33560319 FABP4203980_at −1.3897081 8.03922119 −6.4609935 1.24E−07 0.001003067.15838496 — 240076_at −1.2154985 8.47153306 −6.4502687 1.28E−070.00100306 7.12879005 COL6A1 213428_s_at −1.1799797 9.17734162−6.5227006 1.02E−07 0.00100306 7.3284926 SLC39A8 209267_s_at −1.140995610.4538343 −6.3855772 1.58E−07 0.00107772 6.95009387 MGC5618 221477_s_at−1.1617675 10.5471179 −6.2424898 2.48E−07 0.00135843 6.55382496 SLC39A8219869_s_at −1.14866 10.1877186 −6.2694824 2.28E−07 0.001358436.62867956 — 226218_at −1.2937342 7.33564432 −6.1059571 3.84E−070.00140732 6.17456221 STEAP1 205542_at −1.198521 7.98610593 −6.08528414.10E−07 0.00140732 6.11705174 CHST11 219634_at −1.1616563 9.51077621−6.0764318 4.21E−07 0.00140732 6.09241933 CD9 201005_at −1.148001510.9097322 −6.0774378 4.20E−07 0.00140732 6.09521866 TNF5F13B223502_s_at −1.137131 10.6086468 −6.1814333 3.02E−07 0.001407326.38434731 LACTB 226354_at −1.1146026 10.6969136 −6.1724213 3.10E−070.00140732 6.35931437 ARL6IP5 200761_s_at −1.1108957 11.9357889−6.0645684 4.38E−07 0.00140732 6.05940234 NFKBIE 203927_at −1.164640910.0523732 −5.9997498 5.38E−07 0.00157615 5.87889643 SLIC1 228869_at−1.1244476 10.0277009 −5.994027 5.48E−07 0.00157615 5.86295139 MMP1204475_at −1.5039262 6.32353561 −5.9312361 6.69E−07 0.001741565.68791885 SOD2 215223_s_at −1.2035944 9.66361398 −5.9462273 6.38E−070.00174156 5.72972041 NFKBIA 201502_s_at −1.1701699 11.8415908−5.9153553 7.04E−07 0.0017486 5.64362855 ADAMDEC1 206134_at −1.18611998.53747931 −5.7927992 1.04E−06 0.00247065 5.30158178 MPEG1 226841_at−1.141713 9.90354597 −5.7187643 1.32E−06 0.00281664 5.09479213 ANXA2P2208816_x_at −1.1086074 11.6486476 −5.7130844 1.34E−06 0.002816645.07892372 — 244434_at −1.2846909 6.48107186 −5.6742369 1.52E−060.00284109 4.97038261 CCL2 216598_s_at −1.2516796 11.2421198 −5.66538251.56E−06 0.00284109 4.94564092 ISG20 204698_at −1.2176821 6.18754674−5.677111 1.50E−06 0.00284109 4.97841335 MTSS1 203037_s_at −1.213269711.5042636 −5.6909681 1.44E−06 0.00284109 5.0171321 IFNGR1 211676_s_at−1.1076638 12.1480464 −5.6472459 1.65E−06 0.0029127 4.89496045 —230795_at −1.1702144 9.26991641 −5.6333398 1.73E−06 0.002949264.85610012 NFE2L3 236471_at −1.3257415 5.26403664 −5.6026446 1.90E−060.00315306 4.77032024 CD36 209555_s_at −1.1414722 9.39991418 −5.54828882.26E−06 0.00363742 4.61841752 CYLD 221903_s_at −1.1207309 9.54523467−5.5045621 2.60E−06 0.00406002 4.49622693 ICAM1 202638_s_at −1.40849296.8285265 −5.4886851 2.73E−06 0.00415135 4.45186392 KIAA1505 227265_at−1.1673293 9.93164349 −5.4623712 2.97E−06 0.00423964 4.37834442 BID227143_s_at −1.1112086 11.5740779 −5.471422 2.89E−06 0.004239644.40363069 BID 211725_s_at −1.1017724 11.8106494 −5.4568423 3.02E−060.00423964 4.36289801 IL10 207433_at −1.2783883 5.71640286 −5.38017913.86E−06 0.00508408 4.14877517 ANXA2 201590_x_at −1.1067663 13.1932317−5.3762172 3.91E−06 0.00508408 4.13771284 TNFAIP6 206026_s_at −1.25336045.46505459 −5.3471287 4.28E−06 0.00544542 4.0565035 CD14 201743_at−1.1688628 9.56313815 −5.3162757 4.72E−06 0.00586803 3.97039297 ICAM1202637_s_at −1.253703 7.7078627 −5.2602772 5.64E−06 0.006745793.81417837 ANXA2 210427_x_at −1.1021711 13.1600502 −5.2581893 5.68E−060.00674579 3.80835622 SYNJ2 212828_at −1.1079961 9.8266126 −5.22592696.29E−06 0.00731141 3.71841109 GLIPR1 226142_at −1.1476518 8.96232728−5.2116592 6.57E−06 0.00744619 3.67864746 ECOP 238604_at −1.12918459.93048271 −5.2069623 6.67E−06 0.00744619 3.66555947 CD40 205153_s_at−1.1516665 8.96773222 −5.1878467 7.09E−06 0.00775153 3.61230284 IFIH1219209_at −1.1839872 8.4216604 −5.1481808 8.03E−06 0.0086134 3.50184783IL4I1 230966_at −1.2886142 10.7302425 −5.1035983 9.25E−06 0.009539713.3777992 MAFB 218559_s_at −1.1661498 12.5070822 −5.0783026 1.00E−050.01013992 3.30746517 DAB2 201278_at −1.1002534 9.40858428 −5.07047541.03E−05 0.01020405 3.28570957 P2RX4 204088_at −1.11462 10.5804136−5.0589302 1.06E−05 0.01039288 3.25362692 MLF1 204784_s_at −1.16292489.99075341 −5.0382007 1.14E−05 0.01089897 3.19604331 STATH 206835_at−1.2217631 10.6277925 −4.9970174 1.29E−05 0.01198544 3.08172746 GIMAP8235306_at −1.1769391 7.15724646 −4.9534429 1.48E−05 0.013292672.96090645 TATDN3 235069_at −1.1552651 9.09091742 −4.9541849 1.48E−050.01329267 2.96296263 SYNJ2 216180_s_at −1.1540719 8.13588041 −4.9291941.60E−05 0.01372355 2.89373383 TREM1 219434_at −1.1280034 11.1714599−4.9272524 1.61E−05 0.01372355 2.88835722 ANXA2 213503_x_at −1.100387513.1627385 −4.8992037 1.76E−05 0.01434614 2.81072248 G0S2 213524_s_at−1.1355006 8.75639391 −4.864242 1.96E−05 0.01577044 2.71404776 IL10RA204912_at −1.1199911 10.5172379 −4.8323374 2.17E−05 0.017172682.62592271 BIRC3 210538_s_at −1.257364 4.57445587 −4.8159991 2.28E−050.01765329 2.58083111 NT5E 203939_at −1.2383789 8.45460557 −4.81435912.29E−05 0.01765329 2.57630644 CCL5 1555759_a_i −1.0910656 13.6361191−4.8032103 2.37E−05 0.01802488 2.54555373 SRPX2 205499_at −1.2245126.16138512 −4.767627 2.65E−05 0.01937153 2.4474847 ARL6IP5 200760_s_at−1.1107109 11.7204466 −4.7591181 2.72E−05 0.01959427 2.42405329 EBI3219424_at −1.1775996 7.06372735 −4.7474062 2.82E−05 0.019765542.39181393 CD40 215346_at −1.1705995 8.77095715 −4.7439006 2.86E−050.01976554 2.38216714 SRA1 224130_s_at −1.094757 10.8027383 −4.74427032.85E−05 0.01976554 2.38318441 — 238501_at −1.2105582 5.44953239−4.73925 2.90E−05 0.01977223 2.36937124 SLIC1 229045_at −1.15478868.27898536 −4.7357646 2.93E−05 0.01977223 2.35978293 C5ORF13 238411_x_at−1.1683694 3.79974787 −4.7297145 2.98E−05 0.01979262 2.34314234 CARD15220066_at −1.1393689 8.86627619 −4.7275995 3.00E−05 0.019792622.33732587 PLEKHO1 218223_s_at −1.1393641 9.19617144 −4.7232262 3.05E−050.01982503 2.32530094 NFE2L3 204702_s_at −1.1949945 6.87002251−4.7001908 3.27E−05 0.02069819 2.26199661 P2RY5 218589_at −1.17199029.42743243 −4.6980902 3.29E−05 0.02069819 2.25622666 P5CDBP 209606_at−1.1833853 8.14303401 −4.6940285 3.34E−05 0.02072301 2.24507189 PTX3206157_at −1.1323376 11.2731131 −4.6853648 3.43E−05 0.0210494 2.22128475GHRL 223862_at −1.184681 7.10722772 −4.6529266 3.79E−05 0.022520982.13230051 SGIP1 223672_at −1.1713796 8.75400755 −4.6556052 3.76E−050.02252098 2.13964377 RPL13 /// LO

214976_at −1.1498626 6.91302234 −4.6576183 3.73E−05 0.022520982.14516306 C13ORF31 1553141_at −1.2240082 8.3027252 −4.6445617 3.89E−050.02286455 2.10937474 — 228573_at −1.0954948 10.1938031 −4.6318334.05E−05 0.02353205 2.07450537 — 213891_s_at −1.1613505 8.36985954−4.6072376 4.37E−05 0.02435882 2.00718586 C9ORF130 227893_at −1.14666027.47771908 −4.6095058 4.34E−05 0.02435882 2.01339098 VPS33A 204590_x_at−1.1717826 7.44063872 −4.5964894 4.51E−05 0.0246793 1.97779156 LACTB1552486_s_at −1.1146334 9.43978855 −4.5992016 4.48E−05 0.02467931.98520746 RAB27B 228708_at −1.2146134 8.64471961 −4.5896791 4.61E−050.02495536 1.95917448 FXYD2 207434_s_at −1.2391134 6.87935784 −4.57210484.87E−05 0.02609092 1.91116075 SOD2 216841_s_at −1.1587002 8.29547849−4.5601654 5.05E−05 0.02658149 1.87856531 INADL 214493_s_at −1.18760145.13104061 −4.5382854 5.40E−05 0.02787086 1.81888217 BID 204493_at−1.0962323 11.1430522 −4.5406927 5.36E−05 0.02787086 1.82544538 BTG1240347_at −1.1577464 6.46143817 −4.5117153 5.86E−05 0.029418341.74649575 CENTA2 219358_s_at −1.1328376 10.4221094 −4.5125118 5.85E−050.02941834 1.74866433 LOC54103 213142_x_at −1.1327449 10.7990817−4.5010122 6.06E−05 0.02985684 1.71736561 — 232297_at −1.13964838.4593218 −4.4977208 6.12E−05 0.02989176 1.7084108 THBD 203887_s_at−1.0860181 12.8670409 −4.4922535 6.23E−05 0.02996581 1.6935397 KYNU210663_s_at −1.1273404 10.5827862 −4.4730592 6.61E−05 0.031240791.64136616 TATDN3 228867_at −1.0979673 8.53193411 −4.4719767 6.63E−050.03124079 1.6384252 ITGB5 201125_s_at −1.1305667 9.66682508 −4.46632796.74E−05 0.03151651 1.62308225 HNRPLL 225386_s_at −1.088481 10.9979975−4.4607622 6.86E−05 0.03178871 1.60796956 CRYBB2 206777_s_at −1.12737489.09050704 −4.4486878 7.12E−05 0.03248173 1.57520029 CD55 1555950_a_i−1.101176 11.0430169 −4.4455718 7.19E−05 0.03248173 1.56674717 MPEG1226818_at −1.102944 9.97050985 −4.4364675 7.39E−05 0.03312876 1.54205788POPDC3 219926_at −1.2923154 6.73431127 −4.4296067 7.55E−05 0.033334291.52346112 PLAUR 214866_at −1.1197536 10.1465619 −4.4291541 7.56E−050.03333429 1.52223465 MGLL 239914_at −1.1755243 5.02263039 −4.41926317.79E−05 0.03354952 1.49543825 EBI2 205419_at −1.1647466 10.3787766−4.4209004 7.75E−05 0.03354952 1.49987275 TP5AB1 /// T 207741_x_at−1.154419 7.49088254 −4.4208416 7.76E−05 0.03354952 1.49971361 SLAMF8219386_s_at −1.1604525 10.1187042 −4.4123213 7.96E−05 0.033706051.47664099 VSNL1 203797_at −1.1465556 9.26432896 −4.4080282 8.07E−050.03370605 1.46501964 ICAM2 213620_s_at −1.129714 7.80787761 −4.40830368.06E−05 0.03370605 1.46576519 KYNU 217388_s_at −1.1268071 11.2241113−4.4076297 8.08E−05 0.03370605 1.4639412 ARHGAP18 225166_at −1.18540127.40195979 −4.3979297 8.32E−05 0.03445978 1.43769541 MITF 226066_at−1.1771138 7.94053593 −4.3803753 8.78E−05 0.03578326 1.39023722 MXD1226275_at −1.1272655 8.58697195 −4.3782779 8.84E−05 0.035783261.38457024 — 241389_at −1.1324551 7.7082004 −4.3740983 8.95E−050.03597723 1.37327956 EGF 206254_at −1.2273072 5.23328013 −4.34450519.80E−05 0.03909529 1.29342221 MALT1 210017_at −1.1361187 7.85916694−4.3417635 9.88E−05 0.03913824 1.28603152 AKR1C2 211653_x_at −1.2145869.21551731 −4.3261491 0.00010361 0.03933789 1.24396403 LPAAT-THETA224480_s_at −1.2033448 8.82402466 −4.3329062 0.00010149 0.039337891.26216342 MFI2 235911_at −1.1178645 10.2132798 −4.3339031 0.000101180.03933789 1.26484915 ARHGAP18 225171_at −1.1011604 10.7603262 −4.3299860.0001024 0.03933789 1.25429744 TXNL2 209080_x_at −1.0905642 11.1937357−4.3267122 0.00010343 0.03933789 1.24548038 CD55 201926_s_at −1.087642811.0124454 −4.3312016 0.00010202 0.03933789 1.25757168 ADAM9 202381_at−1.1288776 10.068453 −4.2795249 0.00011941 0.04461757 1.11860933 OS8PL11218304_s_at −1.1200967 8.80861724 −4.268338 0.00012355 0.044617571.08859065 C5ORF32 224797_at −1.1088424 9.60174121 −4.2676443 0.000123810.04461757 1.08672987 CD300A 209933_s_at −1.0919093 11.068246 −4.27798180.00011998 0.04461757 1.11446708 ATP2C1 237278_x_at −1.1252002 4.516837−4.2604681 0.00012654 0.04474124 1.06748681 TGM5 207911_s_at −1.098572910.9973837 −4.255458 0.00012848 0.04474124 1.05405768 CAST 208908_s_at−1.0958388 10.4613552 −4.2557149 0.00012838 0.04474124 1.05474617TNFRSF9 207536_s_at −1.1669411 6.64800587 −4.2459826 0.000132220.04518347 1.02867283 HMGB2 243368_at −1.1602025 4.88716386 −4.24631690.00013209 0.04518347 1.02956814 TNFAIP3 202644_s_at −1.125318710.6490533 −4.2484635 0.00013123 0.04518347 1.03531746 C1ORF21223125_s_at −1.1101543 11.0658204 −4.2399019 0.00013469 0.045738951.01239127 — 212387_at −1.148179 7.86470579 −4.2245512 0.00014110.04762227 0.97132047 12 hr: PRDM1 228964_at −1.3131187 7.67111264−8.6246024 1.41E−10 7.72E−06 11.3048141 RCSD1 239328_at −1.29178049.91539671 −6.452108 1.22E−07 0.0033307 6.31495199 BTG1 240347_at−1.2562187 6.63516956 −5.7047112 1.33E−06 0.02422499 4.46209908 FBXO45225099_at 1.13350791 9.69247626 5.51958363 2.40E−06 0.032821963.99779146 ZNF566 240239_at 1.20902406 6.20206745 5.35216774 4.09E−060.04477351 3.57707114 24 hr: MMP9 203936_s_at −1.2587837 8.76550502−6.6308842 7.89E−08 0.00431641 6.0372842 Downregulated: 6 hr: LOC6483421569392_at 1.25828385 6.46339373 5.71764607 1.32E−06 0.002816645.09166798 BTBD14A 243431_at 1.31196093 8.69387594 5.37680876 3.90E−060.00508408 4.13936456 SERPINB2 204614_at 1.25751853 10.73889225.14040426 8.23E−06 0.00865761 3.48020227 MYB 204798_at 1.0989772913.1513017 5.00361266 1.27E−05 0.01194194 3.10002645 STT3B 238303_at1.2645975 6.00460112 4.9254338 1.62E−05 0.01372355 2.88332163 HSPD1241716_at 1.30689927 6.02121553 4.9223221 1.64E−05 0.01372355 2.87470616ACTN4 232058_at 1.19228742 8.60657642 4.91815847 1.66E−05 0.013723552.86317939 FAM62A 244234_at 1.14840119 7.29749849 4.78192868 2.54E−050.01899888 2.48688527 HIC2 1559600_at 1.17980654 8.38342055 4.767034292.66E−05 0.01937153 2.4458524 OXCT2 235275_at 1.16642629 12.33002014.71420617 3.13E−05 0.02014951 2.30050545 — 228907_at 1.175992778.21884465 4.6120071 4.30E−05 0.02435882 2.02023432 GAPDHS 222280_at1.1646993 7.71035699 4.60723903 4.37E−05 0.02435882 2.00718978 SPFH1202441_at 1.12657525 11.0883546 4.55979394 5.06E−05 0.026581491.87755147 NAPB 1570441_at 1.20267749 5.92073389 4.52611168 5.61E−050.02866712 1.78570418 HNRPD 213359_at 1.16888386 9.72519123 4.503409986.02E−05 0.02985684 1.72389004 CISH 223377_x_at 1.09133621 9.011051344.49116936 6.25E−05 0.02996581 1.69059129 SFRS14 64371_at 1.124005128.1962891 4.44643142 7.17E−05 0.03248173 1.5690791 C14ORF10 239188_at1.16314645 6.54891766 4.38855767 8.56E−05 0.03519643 1.4123519 —232903_at 1.21778341 6.93050721 4.29620676 0.0001135 0.042798811.16341547 HDAC4 232225_at 1.14445571 7.77327378 4.27489999 0.000121110.04461757 1.10619611 CLK1 214683_s_at 1.160507 9.27028645 4.2686560.00012343 0.04461757 1.08944366 CRLF3 235803_at 1.19940674 9.071131334.2670238 0.00012404 0.04461757 1.08506571 ZNF250 241738_at 1.113895984.2390353 4.26401964 0.00012518 0.04473242 1.07700912 WDFY1 234157_at1.20859908 6.39798409 4.25895039 0.00012712 0.04474124 1.06341818 12 hr:FBXO45 225099_at 1.13350791 9.69247626 5.51958363 2.40E−06 0.032821963.99779146 ZNF566 240239_at 1.20902406 6.20206745 5.35216774 4.09E−060.04477351 3.57707114

indicates data missing or illegible when filed

TABLE 4b Probioglat expression values for key genes compared to therange set by observed expression values under Copaxone ® treatmentCopaxone Expression Value Range Probioglat Expression Values Maxi- Mini-Sample Sample Sample Sample Sample Sample Probeset Gene mum mum 1 2 3 45 6 203936_s_at MMP9 9.97 9.53 10.14 10.05 10.12 10.14 10.04 10.04201743_at CD14 9.69 9.32 9.75 9.75 9.67 9.79 9.71 9.86 202637_s_at ICAM18.06 7.44 8.14 7.96 8.26 7.84 8.18 7.92 202638_s_at ICAM1 7.30 6.51 7.677.54 7.45 7.32 7.19 6.94 223961_s_at CISH 7.69 7.24 7.31 7.20 7.41 7.377.62 7.23 223377_x_at CISH 9.11 8.86 8.81 8.81 8.82 8.85 8.84 8.88 Redtext indicates that the expression value for this Probioglat treatedsample is outside of the observed range of all Copaxone samples.

Discussion Example 2 Pro-Inflammatory Genes

Gene-level differentiation analysis identifies specific pro-inflammatorymarkers when comparing Probioglat to Copaxone®. Upon comparison of GAwith Probioglat, significant gene-expression differences were seen(Table 3). Only one batch of Probioglat was available to compare to thefour batches of GA, prohibiting the possibility to study batch-to-batchvariability. However, the range of variation defined by the four GAbatches represents a range of variation that has been demonstrated to besafe and effective by Copaxone®'s clinical trials. The fact that anysingle batch of Probioglat results in values outside of that range (asillustrated in Table 4b and FIG. 44), coupled with lack of PK or PDmarkers to determine equivalence of the two glatiramoids, warrantsfurther investigation.

The consistent confirmatory results obtained by single-probeset, pathwayand independent qRT-PCR analysis are particularly robust, given thestringent statistical framework employed. It should be noted that fewergenes were significantly modulated by GA relative to Probioglat than byGA relative to mannitol, an observation expected given the intendedmimicry of structure between the compounds. Indeed many genes weremodulated in the same direction by both GA and Probioglat versuscontrol, but to differing extents (the cases for many genes discussedbelow, except where noted). It is striking that differences wereobserved between branded GA and the designed purported generic,Probioglat. Two drugs cannot be said to have identical effects ifsignificant differences are manifest. Importantly, the significantdifferences in gene expression observed between Probioglat and Copaxone®were seen in genes tied to highly relevant disease pathoetiology andknown GA mode of action (MOA). Bioinformatic analysis of differentiallyexpressed genes (by FDR corrected p value) following Probioglat versusCopaxone® stimulation of human monocytes at 6 hours identified a numberof genes tied to important immune system functions, in particularinflammation: CCL5, CCL2, MMP9, MMP1, CXCL10, CD14, ICAM1 and BIRC3.Several of these genes have been reported in the literature as modulatedby GA treatment in patients.

-   -   1. CCL5 (RANTES) is a key chemokine thought to attract        inflammatory immune cells to the CNS, and was significantly        upregulated in Probioglat treatment relative to Copaxone®        treatment at 6 hours (FDR adjusted p value 0.018, FC 1.09 in        gene expression analysis; p value 4e-5, FC 1.12 in qRT-PCR        confirmation). Indeed, an antibody blocking CCL5 was shown to        reduce disease metrics including immune infiltration into the        CNS in a viral MS model (Glass et al, Immunol Res, 2004;        Chirstensen et al. Mult. Scler. J. 2013). Expression of the CCL5        receptor, CCR5, on GA-reactive T cells from MS patients was        shown to be downregulated by chronic (1 year) GA treatment        (Allie et al, Arch Neurol 2005; Kouwenhoven et al. J.        Neuroimmunol. 2002). This gene was tested and confirmed to be        upregulated with Probioglat treatment relative to GA treatment        in primary human monocytes (p<0.029, FC 1.53).    -   2. Expression of MMP9 (Matrix Metalloproteinase 9) was        significantly higher with Probioglat versus GA stimulation at 6h        (FDR-adjusted p-value 2.8e-6, FC 1.29 in gene-expression        analysis, FIG. 41a ; p-value 0.02, FC 1.24 in qRT-PCR        confirmation), and at 24h (FDR-adjusted p-value 0.004, FC 1.25).        The MMP9 gene was also upregulated with Probioglat relative to        GA treatment in primary human monocytes (p<0.009, FC 1.4). This        protein is reported to increase access of immune cells to the        CNS by contributing to disruption of the blood brain barrier        (BBB) (Rosenberg et al, The Lancet 2005), and high levels of        MMP9 have been associated with Multiple Sclerosis (Christensen        et al, Mult. Scler 2013; Milward et al., J. Neuroimmunol. 2008;        Knop et al, Neurology 2013; Parks et al, Nat. Rev. Immunol        2004). MMP9 was upregulated with Probioglat relative to        Copaxone® stimulation at 6 hours (FDR adjusted p value 2.8e-6 in        gene expression analysis; p value 0.02 in qRT-PCR confirmation).        Expression levels of MMP9 at both the mRNA and protein level        were increased in immature dendritic cells from MS patients        relative to healthy controls (Kouwenhoven et al, J Neuroimmunol        2002). Elevated MMP9 levels were reported in patients with        gadolinium-enhancing lesions relative to patients without        (Waubant et al, Dis Markers 2006; Antonelli et al, Autoimmun.        Rev. 2014), and MMP9 has been proposed as a biomarker for both        MS diagnosis and progression (Milward et al, J Neuroimmunol        2008; Peperzak et al, J. Immunol. Batim. Md 1950, 2013). GA has        been reported to inhibit MMP9 expression in healthy human        peripheral blood mononuclear cells (PBMC) (Knop et al, Neurology        2013 (Meeting Abstract); Adrem and Ulevitch, Nature 2000).        Increased expression of MMP9 for Probioglat relative to        Copaxone® at multiple timepoints (FIG. 7).    -   3. The level of MMP1, another matrix metalloproteinase gene, was        increased after Probioglat stimulation compared to Copaxone® at        6 hours (FDR adjusted p value 0.002, FC 1.50 in gene expression        analysis; p value 0.02, FC 1.25 in qRT-PCR confirmation). Matrix        metalloproteinases are known to cleave pro-inflammatory        cytokines and chemokines to regulate inflammation (Parks et al,        Nat Rev Immunol, 2004; Baumann et al, J. Exp. Med. 2010). Levels        of MMP1 mRNA, as well as secreted MMP1, were observed to be        higher in immature dendritic cells from MS patients relative to        healthy controls (Kouwenhoven et al, J Neuroimmunol 2002; Parks        et al, Nat Rev Immunol, 2004).    -   4. Expression of the chemokine CXCL10 was increased by        Probioglat stimulation compared to Copaxone® at 6 hours (FDR        adjusted p value 0.0006, FC 1.46 in gene expression analysis; p        value 0.0029, FC 2.28 in qRT-PCR confirmation). This finding was        confirmed by qRT-PCR in primary human monocytes, where CXCL10        was upregulated by Probioglat relative to Copaxone treatment        with p value<0.02 and fold change of 2.1. CXCL10 level in        peripheral fluids was previously shown as associated with host        immune response, particularly with regard to Th-1 cells        (Antonelli et al, Autoimm. Rev., 2014; Natarajan et al, J.        Nueroimmunol. 2013). CXCL10 is involved in recruiting CD8+ and        Th1 CD4+ effector T cells to sites of inflammation (Peperzak et        al, J Immunol, 2013; Hedegaard et al, PLoS ONE 2011). A study        using monocytes from RRMS patients demonstrated CXCL10 to be        increased by GA therapy within the first two months of treatment        (Thamilarasan et al, J Neuroinflammation 2013; Rosenberg, The        Lancet 2005).    -   5. CD14 is a marker of monocyte activation known to enhance        inflammatory responses. CD14 was upregulated in human monocytes        stimulated by Probioglat versus Copaxone 6 hours (FDR adjusted p        value 0.006, FC 1.17; qRT-PCR not tested; FIG. 41b ). CD14 was        not modulated by GA treatment versus mannitol control. This        marker of monocyte activation enhances inflammatory responses        (Mycko et al, Ann. Neurol. 1998). In complex with LPS binding        protein (LBP), CD14 interacts with LPS and helps to present it        to toll-like receptor 4 (TLR4), activating downstream expression        of inflammatory genes via NF-kB (Park et al, Exp Mol Med, 2013).        CD14 has also been shown to be a coreceptor for other TLRs, and        was demonstrated to be required for induction of proinflammatory        cytokines via TLR7 and TLR9 in mouse and human cells in vitro        (Baumann et al, J Exp Med, 2010; Bullard et al, J. Immunol.        2007). Increased expression of CD14 for Probioglat was        determined relative to Copaxone® (FIG. 8).    -   6. CARD15 (NOD2), another gene upregulated by Probioglat versus        Copaxone at 6 hours (FDR adjusted p value 0.02, FC 1.14; qRT-PCR        not tested), is also a key player in the immune response to LPS,        participating in activation of NF-kB. Activation of NOD2 by        peptidoglycan has been shown to induce CNS demyelination in rats        (Natarajan et al, 2013; Sellner et al, Clin. Exp. Immunol.        2013). In addition, a SNP in NOD2 was shown to affect the        responses of Th2 and Th17 cells to myelin basic protein (MBP) in        MS (Hedegaard et al, 2011; Bertrand et al, Immunity 2009).    -   7. BIRC3 expression was increased by Probioglat relative to        Copaxone® at 6 hours (FDR adjusted p value 0.018, FC 1.26;        qRT-PCR not tested). This gene codes for an Inhibitor of        Apoptosis Protein (IAP-1), which in addition to its role in cell        survival plays a role in both innate immunity (Bertrand, 2009;        Kearny et al, J. Biol. Chem. 2013) and inflammation (Labbe et        al, 2011; Ashburner et al, Nat. Genet. 2000), and has been        suggested to have an immunomodulatory effect in autoimmune        demyelination (Hebb et al, 2008; Kanehisa et al, Nucleic Acis        Res. 2000). IAPs including IAP-1 are required for production of        pro-inflammatory cytokines via several different pathways,        including TLR4 activation (Tseng et al, 2010; Zanin-Zhorov et        al, J. Clin. Invest. 2006) and NOD2 activation by TNFα (Kearney        et al, JBC, 2012; Qin et al, Proc. Natl. Acad. Sci. 2012).        -   CCL2 (MCP-1) is another pro-inflammatory cytokine that was            also expressed significantly more highly with Probioglat            treatment relative to Copaxone at 6 hours (FDR adjusted p            value 0.003, FC 1.25; qRT-PCR not tested). CCL2 expression            was decreased by GA treatment relative to mannitol control,            and decreased to a lesser extent by Probioglat relative to            mannitol control. CCL2 is thought to recruit inflammatory            cells into the CNS in EAE and in MS (Mahad et al, 2006;            Waubant, Dis. Markers 2006). This gene was also confirmed to            be upregulated with Probioglat relative to GA treatment in            primary human monocytes (p<0.009, FC 1.24).    -   8. ICAM1 expression was increased by Probioglat relative to        Copaxone® at 6 hours (FDR adjusted p value 0.004, FC 1.41;        qRT-PCR not tested; FIG. 41c ). ICAM1 is an adhesion molecule        that plays a key role in inflammatory processes by promoting        leukocyte adhesion to the endothelium of the vascular wall, and        is known to have an important role in inflammatory cell        infiltration into the CNS in both EAE and MS (Mycko et al, Ann.        Neurol. 1994; Labbe et al, Immunity 2011). In mice null for        ICAM1, T cells produced significantly less IFNγ and showed much        less infiltration into the spinal cord (Bullard et al, J        Immunol, 2007; Hebb et al, Mult. Scler. Houndmills Basingstoke        Engl. 2008). In PBMC from RRMS patients, ICAM1 levels were        higher versus healthy controls, and chronic treatment with GA        affected surface ICAM1 levels in multiple immune cell types        (Sellner et al, Clin Exp Immunol 2013; Tseng et al, Nat.        Immunol. 2010). Increased expression of ICAM1 for Probioglat was        determined compared to Copaxone® stimulation (FIG. 11).

Anti-Inflammatory Genes

As discussed herein, a number of pro-inflammatory genes and pathwayswere shown to be significantly upregulated by Probioglat as compared toCopaxone®. At the same time, several anti-inflammatory genes weredownregulated by Probioglat stimulation in comparison with Copaxone® at6 hours.

-   -   1. CISH, also known as SOCS (Suppressor of Cytokine Signaling),        was expressed at lower level with Probioglat relative to        Copaxone® at 6 hours (FDR adjusted p value 0.03, FC −1.09; FIG.        41d ). A closely related protein, SOCS3, has been shown in        myeloid cells to protect from EAE, the mouse model of MS, via        deactivating neuroinflammatory responses (Qin et al, PNAS 2012;        Bakshi et al, Expert Opin. THer. Targets 2013). Both present        probesets for this gene were affected in the same direction        (FIG. 12). A SNP in SOCS1, another family member, has been        identified as a risk factor for MS (Towfic et al, PLoS ONE        2014).    -   2. HSPD1, also known as HSP-60 (heat shock 60 kDa protein 1),        was downregulated in Probioglat relative to Copaxone® at 6 hours        (FDR adjusted p value 0.01, FC −1.31). Zanin-Zhorov et al (2006)        showed that HSP60 as well as synthetic peptide derived from        HSP60 act as co-stimulators of Tregs through the TLR2 pathway.        Tregs are immune regulatory cells that inhibit        lympho-proliferation and IFNG and TNF secretion by        pro-inflammatory T cells. Zanin-Zhorov et al concluded that        HSP60 can downregulate adaptive immune responses by upregulating        Tregs. Thus, downregulation of HSPD1 may result in less        inhibition of immune response by Probioglat compared to        Copaxone®.

It should be noted, however, the anti-inflammatory cytokine IL10, knownto be relevant to the GA mechanism of action, was also expressed at ahigher level subsequent Probioglat relative to Copaxone treatment at 6hours (FDR adjusted p value 0.005, FC 1.28). The same observation holdsfor another gene at 6 and 12 hours, PRDM1 (Blimp1) (FDR adjusted p value0.0006 and 7.7e-6, and FC 1.31 and 1.31 respectively), that when deletedresults in inflammatory pathology (Chiang et al, PNAS 2013; Johnson etal, Biostat. Oxf. Engl. 2007). Blimp1 is a target of FOXP3 and is neededfor production of IL10 by Tregs; its expression can also be induced byIL2 and proinflammatory cytokines in Tregs (Cretney et al, Nat Immunol.2011; Leek et al, Surrogate Variabel Analysis 2013). However, it is notclear what these observations would imply for APCs such as monocytes. Itis possible that higher Blimp1 could be an attempted protective responseto a higher inflammatory milieu. A statidtically significant differencein such a mechanistically relevant gene—in either direction—between twotherapeutics intended to be identical presents motivation for furtherstudy.

Example 3 Pathway Enrichment Analysis

Upregulated and downregulated genes were analyzed separately for pathwayenrichment, using DAVID (Huang et al, Nucleic Acids Res 2009).

Pathway enrichment results were visualized using volcano plots, plotting−log p values versus enrichment scores. For GA MOA, to obtain top-genelists of appropriate size (tens-hundreds) for use with DAVID, anabsolute-value-fold-change cutoff of 1.5 and p-value cutoff of 1e-5 wereutilized to obtain gene lists for pathway enrichment at 6h. Forcomparisons between branded GA and Probioglat, upregulated ordownregulated genes with FDR-adjusted p values<0.05 were used forpathway enrichment.

DAVID runs were conducted May 21, 2014. Please note that the GOdatabases are updated daily (as noted on the GOsite:www.geneontology.org/GO.downloads.ontology.shtml) and thereforeperforming the same enrichments on the same genesets may yield slightlyvarying results depending on the run date, as illustrated by thedifferences in Table 6 (results from runs on differing dates usingbroader or more restrictive subsets of GO). Thus, the pathway p valuesmay change slightly between runs conducted at different times; theoverall picture of enriched pathways, however, is expected to remainconsistent. Three time points were tested to identify the fold changeand p value filters were used to obtain top gene lists of appropriatesize (i.e. tens to hundreds) for use with DAVID (Table 5).

No pathways were enriched significantly among downregulated genes,however 106 pathways were enriched significantly (Benjamini corrected pvalue<0.05) among genes upregulated by Probioglat relative to GA,including immune system process (GO:0002376), immune system process(GO:0002376) and immune response (GO:0006955) pathways(Benjamini-corrected p-values 1.5e-5 and 3.3e-4, respectively), and manyother immune system related pathways, such as regulation of lymphocytemediated immunity (GO:0002706, Benjamini-corrected p-value 0.007) and Bcell proliferation (GO:0042100 Benjamini-corrected p-value 0.049) (FIG.10 and Table 6). Multiple significantly enriched pathways were relevantto inflammation, including response to lipopolysaccharide (LPS)(GO:0032496; FIG. 9), regulation of inflammatory response (GO:0050727),regulation of tumor necrosis factor production (GO:0032680), andNOD-like receptor signaling (hsa04621) (Benjamini-corrected p-values of8.7e-4, 0.015, 0.028, and 0.027, respectively). No pathways wereenriched significantly among genes downregulated by Probioglat versusGA.

Genes analyzed for pathway enrichment (Tables 5 and 6), using DAVID(conducted May 21, 2014). Performing the same enrichments on the samegenesets may yield slightly varying results depending on the run date(GO databases are updated daily:www.geneontology.org/GO.downloads.ontology.shtml).

TABLE 5 Human monocyte study: pathways significantly enriched amonggenes significantly upregulated by Copaxone ® relative to mannitol at 6hours. Pathways significantly enriched among top genes modulated by GArelative to mannitol control at 6 hours: Top genes are defined bycutoffs of |FC|>1.5 and p-value<1e−5 to obtain lists of appropriate sizefor use with DAVID. Term P value Fold Enrichment Benjamini Enrichedamong top downregulated genes: GO: 0007275~multicellular 6.94E−062.168367347 0.00270611 organismal development GO: 0048731~system5.04E−06 2.396166134 0.00294797 development GO: 0048513~organ 2.61E−062.760084926 0.00305609 development GO: 0048856~anatomical 3.69E−052.164502165 0.00861537 structure development GO: 0030154~cell 4.49E−052.555555556 0.00871888 differentiation GO: 0032502~developmental3.28E−05 1.984126984 0.00955745 process GO: 0003006~reproductive8.34E−05 6.25 0.01385786 developmental process GO: 0048869~cellular0.00010797 2.410901468 0.0156803 developmental process GO:0009653~anatomical 0.00030745 2.643171806 0.03921862 structuremorphogenesis Enriched among top upregulated genes: GO: 0005886~plasma1.02E−13 2.419799407 2.18E−17 membrane GO: 0031226~intrinsic to 1.09E−113.267558528 7.78E−10 plasma membrane GO: 0016020~membrane 8.59E−121.538151311 9.23E−10 GO: 0005887~integral to 2.42E−11 3.2497030171.04E−09 plasma membrane GO: 0044459~plasma 1.97E−11 2.4037212161.06E−09 membrane part GO: 0005576~extracellular 1.37E−10 2.8238730714.90E−Q9 region GO: 0031224~intrinsic to 4.97E−10 1.683683794 1.53E−08membrane GO: 0004871~signal 1.04E−10 2.537224567 2.51E−08 transduceractivity GO: 0060089~molecular 1.04E−10 2.537224567 2.51E−08 transduceractivity GO: 0004872~receptor 6.20E−11 2.976306146 2.99E−08 activity GO:0044425~membrane 1.40E−09 1.538980298 3.75E−08 part GO: 0016021~integralto 1.98E−09 1.675513671 4.73E−08 membrane GO: 0044421~extracellular3.24E−09 3.610050499 6.97E−08 region part GO: 0004888~transmembrane2.35E−09 3.768030976 3.78E−07 receptor activity GO: 0006955~immune9.81E−10 3.570488309 6.34E−07 response GO: 0009611~response 3.29E−104.097150568 6.39E−07 to wounding GO: 0009605~response 7.26E−103.127282815 7.04E−07 to external stimulus GO: 0002376~immune 1.92E−092.852452609 9.30E−07 system process GO: 0050896~response 2.41E−091.852190811 9.36E−07 to stimulus GO: 00322501~multicellular 7.40E−091.769727444 2.39E−06 organismal process GO: 0050793~regulation 3.28E−083.160728606 9.08E−06 of developmental process GO: 0009897~external5.99E−07 6.496675192 1.17E−05 side of plasma membrane GO:0051239~regulation 7.17E−08 2.791593852 1.54E−05 of multicellularorganismal process GO: 0006952~defense 6.90E−08 3.417964583 1.67E−05response GO: 0006954~inflammatory 8.72E−08 4.475172847 1.69E−05 responseGO: 0031012~extracellular 1.51E−06 5.017117426 2.70E−05 matrix GO:0048583~regulation 1.68E−07 3.612684989 2.96E−05 of response to stimulusGO: 0005578~proteinaceous 2.00E−06 5.309782609 3.07E−05 extracellularmatrix GO: 0009986~cell surface 1.88E−06 4.06706753 3.10E−05 GO:0002682~regulation 3.21E−07 3.763213531 5.19E−05 of immune systemprocess GO: 0005615~extracellular 6.96E−06 3.371290545 9.98E−05 spaceGO: 0048731~system 7.36E−07 1.917675905 0.00010967 development GO:0051707~response 1.25E−06 4.4259178 0.00017294 to other organism GO:0007275~multicellular 2.71E−06 1.742406265 0.00032825 organismaldevelopment GO: 0032101~regulation 2.59E−06 6.287901089 0.00033427 ofresponse to external stimulus GO: 0022610~biological 3.65E−062.940010571 0.00039282 adhesion GO: 0007155~cell 3.47E−06 2.9483866690.00039594 adhesion GO: 0048856~anatomical 4.11E−06 1.7920064430.00041352 structure development GO: 0065008~regulation 5.75E−062.067363531 0.00050661 of biological quality GO: 0007166~cell surface5.31E−06 2.24578872 0.00051425 receptor linked signal transduction GO:0050727~regulation 5.72E−06 8.870431894 0.00052809 of inflammatoryresponse GO: 0006950~response 6.47E−06 1.896821914 0.0005449 to stressGO: 0032502~developmental 9.45E−06 1.642672573 0.00073237 process GO:0031347~regulation 9.45E−06 5.519379845 0.0007628 of defense responseGO: 0009607~response 1.20E−05 3.375586386 0.00089042 to biotic stimulusGO: 0019955~cytokine 1.09E−05 6.970960427 0.00131926 binding GO:0050776~regulation 2.06E−05 4.292850991 0.00147588 of immune responseGO: 0040011~locomotion 2.38E−05 3.210251542 0.00164377 GO:0080134~regulation 2.54E−05 3.700142913 0.00169407 of response to stressGO: 0007626~locomotory 3.53E−05 4.081231576 0.00227722 behavior GO:0002684~positive 4.09E−05 4.024547804 0.00255401 regulation of immunesystem process GO: 0000267~cell 0.00027348 1.99311488 0.00366864fraction GO: 0045028~purinergic 5.12E−05 13.86854232 0.00411604nudeotide receptor activity, G-protein coupled GO: 0001608~nucleotide5.12E−05 13.86854232 0.00411604 receptor activity, G- protein coupledGO: 0004930~G-protein 4.66E−05 4.292644053 0.00449193 coupled receptoractivity GO: 0016502~nucleotide 8.64E−05 12.54772877 0.00594437 receptoractivity GO: 0001614~purinergic 8.64E−05 12.54772877 0.00594437nucleotide receptor GO: 0005626~insoluble 0.00050614 2.1198364350.00638231 friction GO: 0048513~organ 0.00010948 1.845652496 0.00640896development GO: 0002697~regulation 0.00010851 6.009002251 0.00655072 ofimmune effector process GO: 0051384~response 0.00011695 7.0460168230.00664447 to glucocorticoid stimulus GO: 0005624~membrane 0.000640982.128163382 0.00762936 fraction hsa04060:Cytokine- 7.88E−05 3.9108669110.00816277 cytokine receptor interaction GO: 0031349~positive 0.000153376.7584243 0.00822279 regulation of defense response GO: 0048584~positive0.00015308 3.789715034 0.00844122 regulation of response to stimulus GO:0031960~response 0.00017474 6.623255814 0.00911158 to corticosteroidstimulus GO: 0042221~response 0.00023157 1.879298045 0.01115792 tochemical stimulus GO: 0065007~biological 0.00022752 1.235816690.01124356 regulation GO: 0050865~regulation 0.00022283 4.2957437470.01130118 of cell activation GO: 0048545~response 0.000259814.216192937 0.0122074 to steroid hormone stimulus GO: 0006935~chemotaxis0.00027256 4.651162791 0.01249951 GO: 0042330~taxis 0.000272564.651162791 0.01249951 GO: 0002703~regulation 0.0003028 7.4299344070.01355657 of leukocyte mediated immunity GO: 0002822~regulation0.00034918 7.244186047 0.01492816 of adaptive immune response based onsomatic recombination of immune receptors built from immunoglobulinsuperfamily domains G0: 0001568~blood 0.00034714 3.471867967 0.01517609vessel development G0: 0030154~cell 0.00037713 1.79379845 0.01576601differentiation GO: 0001944~vasculature 0.00039042 3.42764035 0.01597268development G0: 0002819~regulation 0.00040094 7.067498582 0.0160609 ofadaptive immune response GO: 0051241~negative 0.0004538 4.9020807830.01743952 regulation of multicellular organismal GO: 0051704~multi-0.00044925 2.222569065 0.01761538 organism process GO: 0007165~signal0.00048801 1.566926487 0.01837798 transduction GO: 0009617~response0.00051926 4.267561736 0.01917123 to bacterium GO: 0048519~negative0.00057125 1.628669462 0.01993331 regulation of biological process GO:0050864~regulation 0.00056871 8.564554932 0.0202092 of B cell activationGO: 0001525~angiogenesis 0.00056006 4.224015187 0.02027648 GO:0048869~cellular 0.00059519 1.735654039 0.02039329 developments processGO: 0002694~regulation 0.00064956 4.139534884 0.02184996 of leukocyteactivation GO: 0044243~multicellular 0.00070212 20.69767442 0.02319544organismal catabolic process GO: 0030574~collagen 0.00070212 20.697674420.02319544 cataboltc process GO: 0016477~cell 0.00071879 3.2032115170.02334233 migration GO: 0045595~regulation 0.0007682 2.5172847270.02373537 of cell differentiation GO: 0032879~regulation 0.00078222.358709335 0.02378398 of localization GO: 0050729~positive 0.0007629511.49870801 0.0239569 regulation of inflammatory response GO:0007186~G-protein 0.00075328 2.725619677 0.0240464 coupled receptorprotein signaling pathway GO: 0051270~regulation 0.00083518 3.6427906980.02498336 of cell motion GO: 0048518~positive 0.0009722 1.5592044240.02858412 regulation of biological process GO: 001816~cytokine0.00105123 7.526427061 0.0299652 production GO: 0007610~behavior0.00104771 2.759689922 0.03031177 GO: 00550878~regulation 0.001177034.87004104 0.03300809 of body fluid levels GO: 0032496~response0.0013154 5.681714546 0.03578575 to lipopolysaccharide GO:0002683~negative 0.0013154 5.681714546 0.03578575 regulation of immuneGO: 0051674~localization 0.00131424 2.989664083 0.03626342 of cell GO:0048870~cell motility 0.00131424 2.989664083 0.03626342 GO:0046903~secretion 0.00139387 3.163975707 0.03684834 GO: 0006928~cellmotion 0.0013811 2.469196246 0.03702169 GO: 0048514~blood 0.001424053.398125651 0.03712585 vessel morphogenesis GO: 0001501~skeletal0.00146721 3.143950545 0.03772332 system development GO:0050867~positive 0.00151961 4.664264658 0.03853451 regulation of cellactivation GO: 0030247~polysaccharide 0.0007648 5.243826948 0.04514181binding GO: 0001871~pattern 0.0007648 5.243826948 0.04514181 binding GO:0004222~metalloendopeptidase 0.00087418 6.148387097 0.04585047 activityGO: 0002698~negative 0.00196103 15.05285412 0.0488232 regulation ofimmune effector process GO: 0002698~positive 0.00201705 6.5361077110.04892898 regulation of response to external stimulus GO:0010033~response 0.00199539 2.03004903 0.04902907 to organic substanceTerm Probesets Enriched among top downregulated genes: GO:0007275~multicellular 207865_S_AT, 41037_AT, 201350_AT, 229638_AT,222162_S_AT, 204457_S_AT, organismal 39966_AT, 52651_AT, 227242_S_AT,227236_AT, 200894_S_AT, 239410_AT, development 217028_AT, 206589_AT,211299_S_AT, 208078_S_AT, 223704_S_AT, 201688_S_AT, 201689_S_AT,216953_S_AT, 201690_S_AT, 229103_AT, 218326_S_AT, 202800_AT,210347_S_AT, 232614_AT, 212558_AT, 206935_AT, 229084_AT, 219497_S_AT,227103_S_AT, 235275_AT, 211919_S_AT, 212097_AT, 206067_S_AT, 243209_AT,207725_AT, 209201_X_AT, 213478_AT, 213568_AT, 211421_S_AT, 221900_AT,222891_S_AT, 203685_AT, 207717_S_AT GO: 0048731~system 207865_S_AT,41037_AT, 201350_AT, 229638_AT, 222162_S_AT, 39966_AT, development52651_AT, 227236_AT, 239410_AT, 217028_AT, 206589_AT, 211299_S_AT,223704_S_AT, 201688_S_AT, 201689_S_AT, 216953_S_AT, 201690_S_AT,229103_AT, 218326_S_AT, 202800_AT, 232614_AT, 210347_S_AT, 212558_AT,206935_AT, 229084_AT, 219437_S_AT, 227103_S_AT, 235275_AT, 211919_S_AT,206067_S_AT, 212097_AT, 243209_AT, 207725_AT, 209201_X_AT, 213478_AT,213568_AT, 211421_S_AT, 221900_AT, 222891_S_AT, 203685_AT, 207717_S_ATGO: 0048513~organ 207865_S_AT, 41037_AT, 201350_AT, 222162_S_AT,52651_AT, 239410_AT, development 217028_AT, 206589_AT, 211299_S_AT,223704_S_AT, 201688_S_AT, 201689_S_AT, 216953_S_AT, 201690_S_AT,229103_AT, 218326_S_AT, 232614_AT, 210347_S_AT, 212558_AT, 206935_AT,229084_AT, 219497_S_AT, 227103_S_AT, 235275_AT, 211919_5_AT,206067_S_AT, 212097_AT, 243209_AT, 207725_AT, 209201_X_AT, 213478_AT,211421_S_AT, 213568_AT, 221900_AT, 203685_AT, 2228911_S_AT, 207717_S_ATGO: 0048856~anatomical 207865_S_AT, 41037_AT, 201350_AT, 229638_AT,222162_S_AT, 39966_AT, structure development 52651_AT, 227236_AT,239410_AT, 217028_AT, 206589_AT, 211299_S_AT, 223704_S_AT, 201688_S_AT,201689_S_AT, 216953_S_AT, 201690_S_AT, 229103_AT, 218326_S_AT,202800_AT, 232614_AT, 210347_S_AT, 212558_AT, 206935_AT, 229084_AT,219497_S_AT, 227103_S_AT, 235275_AT, 211919_S_AT, 206067_S_AT,212097_AT, 243203_AT, 207725_AT, 209201_X_AT, 213478_AT, 213568_AT,211421_S_AT, 221900_AT, 222891_S_AT, 203685_AT, 207717_S_AT GO:0030154~cell 207865_S_AT, 213361_AT, 41037_AT, 229638_AT, 204557_S_AT,39966_AT, differentiation 227236_AT, 217028_AT, 206539_AT, 208078_S_AT,201688_S_AT, 201688_S_AT, 216953_S_AT, 201690_S_AT, 229103_AT,202800_AT, 210347_S_AT, 232614_AT, 212558_AT, 229084_AT, 219497_S_AT,227103_S_AT, 235275_AT, 212097_AT, 206067_S_AT, 211919_S_AT, 207725_AT,209201_X_AT, 213478_AT, 211421_S_AT, 222891_S_AT, 203685_AT GO:0032502~developmental 207865_S_AT, 213361_AT, 41037_AT, 201350_AT,229638_AT, 222162_S_AT, process 204557_S_AT, 39966_AT, 52651_AT,227242_S_AT, 227236_AT, 200894_S_AT, 239410_AT, 217028_AT, 206589_AT,211299_S_AT, 208078_S_AT, 223704_S_AT, 201688_S_AT, 201689_S_AT,216953_S_AT, 201690_S_AT, 229103_AT, 218326_S_AT, 202800_AT,210347_S_AT, 232614_AT, 212558_AT, 206935_AT, 229084_AT, 219497_S_AT,227103_S_AT, 235275_AT, 211919_S_AT, 212097_AT, 206067_S_AT, 243209_AT,207725_AT, 209201_X_AT, 213478_AT, 213568_AT, 211421_S_AT, 221900_AT,222891_S_AT, 203685_AT, 207717_S_AT GO: 0003006~reproductive 213361_AT,218326_S_AT, 232614_AT, 222162_S_AT, 204557_S_AT, 206067_S_AT,developmental 211919_S_AT, 200894_S_AT, 209201_X_AT, 217028_AT,203685_AT, 223704_S_AT, process 216953_S_AT GO: 0048869~cellular207865_S_AT, 213361_AT, 41037_AT, 229638_AT, 204557_S_AT, 39966_AT,developmental process 227236_AT, 217028_AT, 206589_AT, 208078_S_AT,201688_S_AT, 201689_S_AT, 216953_S_AT, 201690_S_AT, 229103_AT,202800_AT, 210347_S_AT, 232614_AT, 212558_AT, 229084_AT, 219497_S_AT,227103_S_AT, 235275_AT, 212097_AT, 206067_S_AT, 211919_S_AT, 207725_AT,209201_X_AT, 213478_AT, 211421_S_AT, 222891_S_AT, 203685_AT GO:0009653~anatomical 41037_AT, 222162_S_AT, 526S1_AT, 217028_AT,206589_AT, 201688_S_AT, structure morphogenesis 201689_S_AT,216953_S_AT, 201690_S_AT, 229103_AT, 218326_S_AT, 202800_AT, 232614_AT,229084_AT, 206935_AT, 206067_S_AT, 211919_S_AT, 212097_AT, 243209_AT,207725_AT, 213568_AT, 211421_S_AT, 209201_X_AT, 221900_AT, 203685_ATEnriched among top upregulated genes: GO: 0005886~plasma 219358_S_AT,1553995_A_AT, 210495_X_AT, 229221_AT, 223723_AT, 212298_AT, membrane209555_S_AT, 223660_AT, 211066_X_AT, 219412_AT, 205798_AT, 228579_AT,230360_AT, 226545_AT, 242903_AT, 207610_S_AT, 220307_AT, 226629_AT,201590_X_AT, 203922_S_AT, 229937_X_AT, 214830_AT, 203104_AT, 212977_AT,202756_S_AT, 228766_AT, 230925_AT, 243556_AT, 201005_AT, 201242_S_AT,242907_AT, 209122_AT, 205128_X_AT, 214211_AT, 237252_AT, 214297_AT,202727_S_AT, 221060_S_AT, 211719_X_AT, 223596_AT, 223501_AT, 205898_AT,34210_AT, 205099_S_AT, 218613_AT, 210146_X_AT, 215836_S_AT, 217678_AT,232068_S_AT, 209047_AT, 238581_AT, 1554992_AT, 209906_AT, 243483_AT,210510_S_AT, 211030_S_AT, 211676_S_AT, 208121_S_AT, 238669_AT,204105_S_AT, 219994_AT, 201125_S_AT, 203355_S_AT, 202638_S_AT,201243_S_AT, 204912_AT, 201069_AT, 206206_AT, 228918_AT, 222877_AT,227134_AT, 203217_S_AT, 229900_AT, 244375_AT, 206488_S_AT, 206171_AT,208789_AT, 1553151_AT, 220066_AT, 228640_AT, 237442_AT, 203939_AT,205542_AT, 218589_AT, 243894_AT, 213428_S_AT, 205891_AT, 203665_AT,207542_S_AT, 202748_AT, 208816_X_AT, 239519_AT, 208161_S_AT,221266_S_AT, 209921_AT, 223502_S_AT, 1557938_S_AT, 212086_X_AT,220484_AT, 203887_S_AT, 224341_X_AT, 223939_AT, 206637_AT, 1555756_A_AT,209392_AT, 209993_AT, 215813_S_AT, 201324_AT, 212464_S_AT, 216442_X_AT,213503_X_AT, 227240_AT, 210427_X_AT, 202609_AT, 214724_AT, 226218_AT,204661_AT, 211661_X_AT, 210895_S_AT, 222062_AT, 204116_AT, 232746_AT,223092_AT, 225188_AT, 202827_S_AT, 205419_AT, 235299_AT, 1560960_AT,201952_AT, 225189_S_AT, 1552798_A_AT, 210264_AT, 205718_AT, 237904_AT,203888_AT, 223798_AT, 212096_S_AT, 210258_AT, 210004_AT, 222876_S_AT,229797_AT, 218223_S_AT, 241929_AT, 219434_AT, 201951_AT GO:0031226~intrinsic to 223723_AT, 229221_AT, 209555_S_AT, 223660_AT,203217_S_AT, 206488_S_AT, plasma membrane 206171_AT, 228579_AT,228640_AT, 242903_AT, 205542_AT, 205891_AT, 207542_S_AT, 208161_S_AT,203922_S_AT, 203104_AT, 202756_S_AT, 224341_X_AT, 203887_S_AT,228766_AT, 209392_AT, 201005_AT, 201242_S_AT, 237252_AT, 214297_AT,202727_S_AT, 221060_S_AT, 202609_AT, 223596_AT, 34210_AT, 204661_AT,205898_AT, 205099_S_AT, 211661_X_AT, 222062_AT, 204116_AT, 210146_X_AT,202827_S_AT, 223092_AT, 209047_AT, 205419_AT, 232068_S_AT, 209906_AT,1560960_AT, 211030_S_AT, 210264_AT, 211676_S_AT, 208121_S_AT,1552798_A_AT, 205718_AT, 237904_AT, 203888_AT, 204105_S_AT, 210004_AT,241929_AT, 201125_S_AT, 202638_S_AT, 201243_S_AT GO: 0016020~membrane1553995_A_AT, 223723_AT, 212298_AT, 223660_AT, 222838_AT, 219412_AT,205798_AT, 205960_AT, 228579_AT, 238681_AT, 217997_AT, 226545_AT,227747_AT, 205505_AT, 220307_AT, 226629_AT, 216080_S_AT, 201590_X_AT,203922_S_AT, 218686_S_AT, 221815_AT, 203104_AT, 202756_S_AT, 228766_AT,205128_X_AT, 214211_AT, 214581_X_AT, 63825_AT, 211719_X_AT, 223501_AT,205898_AT, 205099_S_AT, 219574_AT, 210146_X_AT, 215836_S_AT, 235944_AT,209047_AT, 240076_AT, 1554992_AT, 219926_AT, 235458_AT, 211676_S_AT,225842_AT, 238669_AT, 204257_AT, 204105_S_AT, 224989_AT, 206134_AT,202638_S_AT, 239761_AT, 201243_S_AT, 204312_AT, 238638_AT, 228318_AT,227134_AT, 222877_AT, 212062_AT, 202434_S_AT, 222858_S_AT, 204222_S_AT,229900_AT, 241392_AT, 206488_S_AT, 208789_AT, 1553151_AT, 220066_AT,228640_AT, 205542_AT, 213338_AT, 203665_AT, 205891_AT, 202748_AT,208816_X_AT, 239519_AT, 208161_S_AT, 218856_AT, 210145_AT, 223502_S_AT,227889_AT, 236345_AT, 1557938_S_AT, 205003_AT, 212086_X_AT, 223939_AT,203887_S_AT, 206637_AT, 211138_S_AT, 1555756_A_AT, 215813_S_AT,227240_AT, 210427_X_AT, 226218_AT, 204661_AT, 225809_AT, 210895_S_AT,222062_AT, 232746_AT, 210512_S_AT, 225188_AT, 211527_X_AT, 224990_AT,1560960_AT, 201952_AT, 225189_S_AT, 210264_AT, 205718_AT, 210258_AT,210757_X_AT, 222876_S_AT, 210004_AT, 229797_AT, 201280_S_AT, 201951_AT,220333_AT, 219358_S_AT, 210495_X_AT, 229221_AT, 209555_S_AT,202435_S_AT, 211066_X_AT, 217999_S_AT, 224480_S_AT, 242871_AT,214255_AT, 230360_AT, 242903_AT, 228490_AT, 207610_S_AT, 229937_X_AT,214830_AT, 227052_AT, 212977_AT, 230925_AT, 243556_AT, 201005_AT,201242_S_AT, 242907_AT, 209122_AT, 237252_AT, 212171_X_AT, 214297_AT,237030_AT, 202727_S_AT, 221060_S_AT, 223596_AT, 34210_AT, 205566_AT,218613_AT, 217678_AT, 232068_S_AT, 238581_AT, 57715_AT, 209906_AT,243483_AT, 210510_S_AT, 210513_S_AT, 211030_S_AT, 208121_S_AT,223434_AT, 204881_S_AT, 225097_AT, 219994_AT, 205306_X_AT, 203355_S_AT,201125_S_AT, 226136_AT, 201069_AT, 206206_AT, 203217_S_AT, 201278_AT,244375_AT, 206171_AT, 218854_AT, 237442_AT, 203939_AT, 218589_AT,243894_AT, 213428_S_AT, 202436_S_AT, 207542_S_AT, 221565_S_AT,201279_S_AT, 219386_S_AT, 221266_S_AT, 209921_AT, 225337_AT, 220484_AT,224341_X_AT, 228762_AT, 209392_AT, 201324_AT, 209993_AT, 212464_S_AT,1555606_A_AT, 216442_X_AT, 213503_X_AT, 228708_AT, 202609_AT, 214724_AT,211661_X_AT, 214841_AT, 204116_AT, 225207_AT, 219385_AT, 202827_S_AT,223092_AT, 87100_AT, 205419_AT, 235286_AT, 235299_AT, 1554285_AT,202437_S_AT, 1552798_A_AT, 203888_AT, 237904_AT, 223798_AT, 212096_S_AT,218223_S_AT, 241929_AT, 219434_AT GO: 0005887~integral to 223723_AT,229221_AT, 209555_S_AT, 223660_AT, 203217_S_AT, 206488_S_AT, plasmamembrane 206171_AT, 228579_AT, 228640_AT, 242903_AT, 205542_AT,205891_AT, 207542_S_AT, 208161_S_AT, 203922_S_AT, 203104_AT,202756_S_AT, 224341_X_AT, 203887_S_AT, 228766_AT, 209392_AT, 201005_AT,201242_S_AT, 237252_AT, 214297_AT, 202727_S_AT, 221060_S_AT, 202609_AT,223596_AT, 34210_AT, 204661_AT, 205898_AT, 205099_S_AT, 211661_X_AT,222062_AT, 204116_AT, 210146_X_AT, 202827_S_AT, 223092_AT, 209047_AT,205419_AT, 232068_S_AT, 209906_AT, 211030_S_AT, 210264_AT, 211676_S_AT,208121_S_AT, 1552798_A_AT, 205718_AT, 237904_AT, 203888_AT, 204105_S_AT,210004_AT, 241929_AT, 201125_S_AT, 202638_S_AT, 201243_S_AT GO:0044459~plasma 210495_X_AT, 223723_AT, 229221_AT, 209555_S_AT,223660_AT, 227134_AT, membrane part 203217_S_AT, 219412_AT, 205798_AT,206488_S_AT, 244375_AT, 206171_AT, 228579_AT, 208789_AT, 1553151_AT,228640_AT, 237442_AT, 242903_AT, 205542_AT, 203665_AT, 205891_AT,207542_S_AT, 202748_AT, 220307_AT, 208161_S_AT, 203922_S_AT, 214830_AT,1557938_S_AT, 203104_AT, 202756_S_AT, 224341_X_AT, 203887_S_AT,228766_AT, 1555756_A_AT, 230925_AT, 209332_AT, 201005_AT, 201242_S_AT,209993_AT, 242907_AT, 212464_S_AT, 237252_AT, 216442_X_AT, 214297_AT,202727_S_AT, 221060_S_AT, 211719_X_AT, 202609_AT, 214724_AT, 223596_AT,226218_AT, 34210_AT, 204661_AT, 205898_AT, 205099_S_AT, 211661_X_AT,210895_S_AT, 218613_AT, 222062_AT, 204116_AT, 210146_X_AT, 202827_S_AT,223092_AT, 225188_AT, 209047_AT, 205419_AT, 232068_S_AT, 238581_AT,209906_AT, 1560960_AT, 243483_AT, 201952_AT, 225189_S_AT, 211030_S_AT,210264_AT, 211676_S_AT, 208121_S_AT, 1552798_A_AT, 205718_AT, 237904_AT,203888_AT, 204105_S_AT, 210004_AT, 219994_AT, 241929_AT, 203355_S_AT,201125_S_AT, 201951_AT, 202638_S_AT, 201243_S_AT GO:0005576~extracellular 226136_AT, 223221_AT, 223723_AT, 210495_X_AT,201069_AT, 212298_AT, region 205798_AT, 204222_S_AT, 229900_AT,203936_S_AT, 226545_AT, 37145_AT, 203665_AT, 213428_S_AT, 208816_X_AT,239519_AT, 201590_X_AT, 212190_AT, 223502_S_AT, 206157_AT, 212143_S_AT,202458_AT, 203887_S_AT, 202756_S_AT, 201422_AT, 204834_AT, 205495_S_AT,228873_AT, 209392_AT, 228762_AT, 210095_S_AT, 213265_AT, 209122_AT,212464_S_AT, 237252_AT, 216442_X_AT, 237030_AT, 212171_X_AT,213503_X_AT, 204575_S_AT, 1405_I_AT, 210427_X_AT, 211719_X_AT,226218_AT, 223501_AT, 206835_AT, 207433_AT, 227265_AT, 235944_AT,210512_S_AT, 202827_S_AT, 221463_AT, 211527_X_AT, 204475_AT, 235286_AT,217757_AT, 229004_AT, 204655_AT, 210510_S_AT, 210513_S_AT, 203888_AT,210004_AT, 206134_AT, 202087_S_AT, 1555759_A_AT, 1556423_AT, 219434_AT,202638_S_AT GO: 0031224~intrinsic to 220333_AT, 1553995_A_AT, 229221_AT,223723_AT, 212298_AT, 209555_S_AT, membrane 223660_AT, 222838_AT,211066_X_AT, 205798_AT, 224480_S_AT, 214255_AT, 242871_AT, 238681_AT,228579_AT, 230360_AT, 226545_AT, 242903_AT, 227747_AT, 228490_AT,207610_S_AT, 205505_AT, 220307_AT, 226629_AT, 216080_S_AT, 203922_S_AT,218686_S_AT, 229937_X_AT, 221815_AT, 214830_AT, 227052_AT, 203104_AT,212977_AT, 202756_S_AT, 228766_AT, 201005_AT, 201242_S_AT, 214581_X_AT,237252_AT, 237030_AT, 214297_AT, 63825_AT, 202727_S_AT, 221060_S_AT,223596_AT, 223501_AT, 205898_AT, 34210_AT, 205099_S_AT, 205566_AT,219574_AT, 210146_X_AT, 215836_S_AT, 217678_AT, 232068_S_AT, 240076_AT,209047_AT, 57715_AT, 209906_AT, 243483_AT, 210510_S_AT, 211030_S_AT,235458_AT, 219926_AT, 211676_S_AT, 208121_S_AT, 204257_AT, 223434_AT,224989_AT, 204105_S_AT, 204881_S_AT, 206134_AT, 205306_X_AT,201125_S_AT, 202638_S_AT, 239761_AT, 201243_S_AT, 226136_AT, 204912_AT,238638_AT, 206206_AT, 228918_AT, 222877_AT, 203217_S_AT, 212062_AT,229900_AT, 204222_S_AT, 206488_S_AT, 241392_AT, 206171_AT, 218854_AT,228640_AT, 203939_AT, 205542_AT, 213318_AT, 218589_AT, 243894_AT,205831_AT, 207542_S_AT, 221565_S_AT, 239519_AT, 219386_S_AT,208161_S_AT, 221266_S_AT, 209921_AT, 218856_AT, 210145_AT, 227889_AT,223502_S_AT, 225337_AT, 236345_AT, 220484_AT, 203887_S_AT, 224341_X_AT,223939_AT, 206637_AT, 211138_S_AT, 1555756_A_AT, 209392_AT, 228762_AT,209993_AT, 201324_AT, 1555606_A_AT, 228708_AT, 202609_AT, 226218_AT,204661_AT, 225809_AT, 211661_X_AT, 214841_AT, 210895_S_AT, 222062_AT,232746_AT, 204116_AT, 219385_AT, 223092_AT, 202827_S_AT, 205419_AT,87100_AT, 235286_AT, 224990_AT, 235299_AT, 1560960_AT, 1554285_AT,201952_AT, 1552798_A_AT, 210264_AT, 205718_AT, 237904_AT, 203888_AT,223798_AT, 210004_AT, 229797_AT, 241929_AT, 219434_AT, 201951_AT GO:0004871~signal 220333_AT, 204912_AT, 229221_AT, 212298_AT, 209555_S_AT,223660_AT, transducer activity 206206_AT, 222838_AT, 222877_AT,205798_AT, 206488_S_AT, 205960_AT, 206171_AT, 242871_AT, 200878_AT,242903_AT, 218589_AT, 203760_S_AT, 203665_AT, 205891_AT, 207610_S_AT,220307_AT, 239519_AT, 218856_AT, 218686_S_AT, 229937_X_AT, 203104_AT,212977_AT, 223939_AT, 224341_X_AT, 203887_S_AT, 206637_AT, 228766_AT,1555756_A_AT, 209332_AT, 214581_X_AT, 237252_AT, 214297_AT, 202727_S_AT,1405_I_AT, 221060_S_AT, 202609_AT, 214724_AT, 226218_AT, 205898_AT,205099_S_AT, 211661_X_AT, 210895_S_AT, 222062_AT, 204116_AT, 232746_AT,225207_AT, 210146_X_AT, 235944_AT, 205419_AT, 232068_S_AT, 209906_AT,243483_AT, 210510_S_AT, 204655_AT, 214054_AT, 211676_S_AT, 208121_S_AT,1552798_A_AT, 210264_AT, 206675_S_AT, 205718_AT, 203888_AT, 237904_AT,203761_AT, 210258_AT, 210004_AT, 1555759_A_AT, 241929_AT, 201125_S_AT,219434_AT, 202638_S_AT GO: 0060089~molecular 220333_AT, 204912_AT,229221_AT, 212298_AT, 209555_S_AT, 223660_AT, transducer activity206206_AT, 222838_AT, 222877_AT, 205798_AT, 206488_S_AT, 205960_AT,206171_AT, 242871_AT, 200878_AT, 242903_AT, 218589_AT, 203760_S_AT,203665_AT, 205891_AT, 207610_S_AT, 220307_AT, 239519_AT, 218556_AT,218686_S_AT, 229937_X_AT, 203104_AT, 212977_AT, 223939_AT, 224341_X_AT,203887_S_AT, 206637_AT, 228766_AT, 1555756_A_AT, 209392_AT, 214581_X_AT,237252_AT, 214297_AT, 202727_S_AT, 1405_I_AT, 221060_S_AT, 202609_AT,214724_AT, 226218_AT, 205898_AT, 205099_S_AT, 211661_X_AT, 210895_S_AT,222062_AT, 204116_AT, 232746_AT, 225207_AT, 210146_X_AT, 235944_AT,205419_AT, 232068_S_AT, 209906_AT, 243483_AT, 210510_S_AT, 204655_AT,214054_AT, 211676_S_AT, 208121_S_AT, 1552798_A_AT, 210264_AT,206675_S_AT, 205718_AT, 203888_AT, 237904_AT, 203761_AT, 210258_AT,210004_AT, 1555759_A_AT, 241929_AT, 201125_S_AT, 219434_AT, 202638_S_ATGO: 0004872~receptor 220333_AT, 229221_AT, 204912_AT, 212298_AT,209555_S_AT, 223660_AT, activity 206206_AT, 222838_AT, 222877_AT,205798_AT, 206488_S_AT, 206171_AT, 242871_AT, 242903_AT, 218589_AT,205891_AT, 207610_S_AT, 220307_AT, 239519_AT, 218856_AT, 218686_S_AT,229937_X_AT, 203104_AT, 212977_AT, 223939_AT, 224341_X_AT, 203887_S_AT,228766_AT, 206637_AT, 1555756_A_AT, 209392_AT, 214581_X_AT, 237252_AT,202727_S_AT, 221060_S_AT, 202609_AT, 226218_AT, 205898_AT, 205099_S_AT,211661_X_AT, 210895_S_AT, 222062_AT, 204116_AT, 232746_AT, 210146_X_AT,235944_AT, 205419_AT, 232068_S_AT, 209906_AT, 243483_AT, 210510_S_AT,210264_AT, 208121_S_AT, 211676_S_AT, 1552798_A_AT, 205718_AT, 237904_AT,203888_AT, 210004_AT, 241929_AT, 201125_S_AT, 219434_AT, 202638_S_AT GO:0044425~membrane 1553995_A_AT, 220333_AT, 210495_X_AT, 229221_AT,223723_AT, 212298_AT, part 209555_S_AT, 202435_S_AT, 223660_AT,222838_AT, 211066_X_AT, 219412_AT, 205798_AT, 224480_S_AT, 214255_AT,242871_AT, 238681_AT, 228579_AT, 230360_AT, 226545_AT, 227747_AT,242903_AT, 228490_AT, 207610_S_AT, 205505_AT, 220307_AT, 226629_AT,216080_S_AT, 203922_S_AT, 218686_S_AT, 229937_X_AT, 221815_AT,214830_AT, 227052_AT, 203104_AT, 212977_AT, 202756_S_AT, 228766_AT,230925_AT, 201005_AT, 201242_S_AT, 242907_AT 209122_AT, 205128_X_AT,214581_X_AT, 237252_AT, 237030_AT, 214297_AT, 63825_AT, 202727_S_AT,221060_S_AT, 211719_X_AT, 223596_AT, 223501_AT, 205898_AT, 34210_AT,205099_S_AT, 205566_AT, 219574_AT, 218613_AT, 210146_X_AT, 215836_S_AT,217678_AT, 232068_S_AT, 240076_AT, 209047_AT, 238581_AT, 57715_AT,209906_AT, 243483_AT, 210510_S_AT, 211030_S_AT, 235458_AT, 219926_AT,208121_S_AT, 211676_S_AT, 238669_AT, 204257_AT, 223434_AT, 224989_AT,204105_S_AT, 204881_S_AT, 206134_AT, 205306_X_AT, 219994_AT,201125_S_AT, 203355_S_AT, 202638_S_AT, 239761_AT, 201243_S_AT,226136_AT, 204912_AT, 238638_AT, 206206_AT, 228918_AT, 222877_AT,227134_AT, 203217_S_AT, 212062_AT, 202434_S_AT, 222858_S_AT, 201278_AT,229900_AT, 204222_S_AT, 244375_AT, 206488_S_AT, 241392_AT, 206171_AT,218854_AT, 1553151_AT, 208789_AT, 228640_AT, 203939_AT, 237442_AT,205542_AT, 213338_AT, 243894_AT, 218589_AT, 205891_AT, 203665_AT,202436_S_AT, 221565_S_AT, 207542_S_AT, 201279_S_AT, 202748_AT,239519_AT, 219386_S_AT, 208161_S_AT, 221266_S_AT, 209921_AT, 218856_AT,210145_AT, 227889_AT, 223502_S_AT, 225337_AT, 236345_AT, 1557938_S_AT,205003_AT, 220484_AT, 203887_S_AT, 224341_X_AT, 223939_AT, 206637_AT,211138_S_AT, 1555756_A_AT, 209392_AT, 228762_AT, 209993_AT, 201324_AT,215813_S_AT, 212464_S_AT, 1555606_A_AT, 216442_X_AT, 228708_AT,202609_AT, 214724_AT, 226218_AT, 204661_AT, 225809_AT, 211661_X_AT,214841_AT, 210895_S_AT, 222062_AT, 232746_AT, 204116_AT, 219385_AT,223092_AT, 225188_AT, 202827_S_AT, 205419_AT, 87100_AT, 235286_AT,224990_AT, 235299_AT, 1560960_AT, 201952_AT, 1554285_AT, 202437_S_AT,225189_S_AT, 1552798_A_AT, 210264_AT, 205718_AT, 237904_AT, 203888_AT,223798_AT, 210757_X_AT, 210004_AT, 229797_AT, 201280_S_AT, 241929_AT,219434_AT, 201951_AT GO: 0016021~integral to 220333_AT, 229221_AT,223723_AT, 212298_AT, 209555_S_AT, 223660_AT, membrane 222838_AT,211066_X_AT, 205798_AT, 224480_S_AT, 214255_AT, 242871_AT, 238681_AT,228579_AT, 230360_AT, 242903_AT, 227747_AT, 228490_AT, 207610_S_AT,205505_AT, 220307_AT, 226629_AT, 216080_S_AT, 203922_S_AT, 218686_S_AT,229937_X_AT, 221815_AT, 214830_AT, 227052_AT, 203104_AT, 212977_AT,202756_S_AT, 228766_AT, 201005_AT, 201242_S_AT, 214581_X_AT, 237252_AT,237030_AT, 214297_AT, 63825_AT, 202727_S_AT, 221060_S_AT, 223536_AT,223501_AT, 205898_AT, 34210_AT, 205099_S_AT, 205566_AT, 219574_AT,210146_X_AT, 215836_S_AT, 217678_AT, 232068_S_AT, 240076_AT, 209047_AT,57715_AT, 209906_AT, 243483_AT, 210510_S_AT, 211030_S_AT, 235458_AT,219926_AT, 211676_S_AT, 208121_S_AT, 204257_AT, 223434_AT, 224989_AT,204105_S_AT, 204881_S_AT, 206134_AT, 205306_X_AT, 201125_S_AT,202638_S_AT, 239761_AT, 201243_S_AT, 226136_AT, 204912_AT, 238638_AT,206206_AT, 228918_AT, 222877_AT, 203217_S_AT, 212062_AT, 204222_S_AT,206488_S_AT, 241392_AT, 206171_AT, 218854_AT, 228640_AT, 205542_AT,213338_AT, 218589_AT, 243894_AT, 205891_AT, 207542_S_AT, 221565_S_AT,239519_AT, 219386_S_AT, 208161_S_AT, 221266_S_AT, 209921_AT, 218856_AT,210145_AT, 227889_AT, 223502_S_AT, 225337_AT, 236345_AT, 220484_AT,203887_S_AT, 224341_X_AT, 223939_AT, 206637_AT, 211138_S_AT,1555756_A_AT, 209392_AT, 228762_AT, 209993_AT, 201324_AT, 1555606_A_AT,202609_AT, 226218_AT, 204661_AT, 225809_AT, 211661_X_AT, 214841_AT,210895_S_AT, 222062_AT, 232746_AT, 204116_AT, 219385_AT, 223092_AT,202827_S_AT, 205419_AT, 87100_AT, 235286_AT, 224990_AT, 235299_AT,1554285_AT, 201952_AT, 1552798_A_AT, 210264_AT, 205718_AT, 237904_AT,203888_AT, 223798_AT, 210004_AT, 229797_AT, 241929_AT, 219434_AT,201951_AT GO: 0044421~extracellular 237252_AT, 229221_AT, 216442_X_AT,210495_X_AT, 201069_AT, 212171_X_AT, region part 213503_X_AT,204575_S_AT, 1405_I_AT, 210427_X_AT, 211719_X_AT, 223501_AT, 229900_AT,207433_AT, 227265_AT, 203936_S_AT, 235944_AT, 210512_S_AT, 202827_S_AT,221463_AT, 226545_AT, 211527_X_AT, 204475_AT, 235286_AT, 37145_AT,203665_AT, 213428_S_AT, 217757_AT, 229004_AT, 208816_X_AT, 204655_AT,210513_S_AT, 201590_X_AT, 212190_AT, 223502_S_AT, 203888_AT,212143_S_AT, 203887_S_AT, 202756_S_AT, 204834_AT, 205495_S_AT,228873_AT, 1555759_A_AT, 1556423_AT, 210095_S_AT, 202638_S_AT,212464_S_AT GO: 0004888~transmembrane 237252_AT, 204912_AT, 212298_AT,209555_S_AT, 223660_AT, 202727_S_AT, receptor activity 221060_S_AT,222877_AT, 226218_AT, 205898_AT, 205099_S_AT, 211661_X_AT, 205798_AT,206488_S_AT, 222062_AT, 204116_AT, 232746_AT, 206171_AT, 235944_AT,232068_S_AT, 205419_AT, 242903_AT, 218589_AT, 209906_AT, 205891_AT,207610_S_AT, 210510_S_AT, 239519_AT, 210264_AT, 1552798_A_AT,208121_S_AT, 211676_S_AT, 237904_AT, 203888_AT, 203104_AT, 212977_AT,203887_S_AT, 224341_X_AT, 223939_AT, 210004_AT, 228766_AT, 206637_AT,209392_AT, 241929_AT, 202638_S_AT GO: 0006955~immune 214211_AT,202869_AT, 212171_X_AT, 205552_S_AT, 1405_I_AT, 221060_S_AT, response206206_AT, 222838_AT, 226218_AT, 223501_AT, 205099_S_AT, 211661_X_AT,205798_AT, 210895_S_AT, 222062_AT, 204116_AT, 207433_AT, 210146_X_AT,210512_S_AT, 232068_S_AT, 221463_AT, 220066_AT, 205419_AT, 211527_X_AT,238581_AT, 202748_AT, 204655_AT, 210513_S_AT, 1552798_A_AT, 203922_S_AT,229937_X_AT, 223502_S_AT, 206157_AT, 223434_AT, 224341_X_AT, 210004_AT,206637_AT, 1555756_A_AT, 1555759_A_AT, 209392_AT, 219434_AT, 242907_AT,202638_S_AT, 213293_S_AT GO: 0009611~response 210495_X_AT, 229221_AT,212298_AT, 209555_S_AT, 223660_AT, 206206_AT, to wounding 206488_S_AT,206171_AT, 228490_AT, 203665_AT, 239519_AT, 203922_S_AT, 221815_AT,206157_AT, 225337_AT, 224341_X_AT, 203887_S_AT, 228766_AT, 1555756_A_AT,201005_AT, 203060_S_AT, 212464_S_AT, 237252_AT, 216442_X_AT, 63825_AT,1405_I_AT, 221060_S_AT, 211719_X_AT, 205898_AT, 205099_S_AT,211661_X_AT, 205566_AT, 207433_AT, 211026_S_AT, 235944_AT, 221463_AT,87100_AT, 232068_S_AT, 208436_S_AT, 204465_S_AT, 209906_AT, 217757_AT,210510_S_AT, 204655_AT, 1552553_A_AT, 1552798_A_AT, 203888_AT,237904_AT, 210004_AT, 1555759_A_AT, 241929_AT GO: 0009605~response229221_AT, 210495_X_AT, 212298_AT, 209555_S_AT, 223660_AT, 206206_AT, toexternal stimulus 222877_AT, 206488_S_AT, 206171_AT, 202284_S_AT,220066_AT, 228490_AT, 203665_AT, 205831_AT, 239519_AT, 203922_S_AT,210145_AT, 206157_AT, 221815_AT, 225337_AT, 224341_X_AT, 203887_S_AT,228766_AT, 1555755_A_AT, 209392_AT, 203060_S_AT, 201005_AT, 212464_S_AT,237252_AT, 216442_X_AT, 63825_AT, 1405_I_AT, 221060_S_AT, 211719_X_AT,205898_AT, 205099_S_AT, 211661_X_AT, 205566_AT, 207433_AT, 211026_S_AT,235944_AT, 202827_S_AT, 208436_S_AT, 221463_AT, 87100_AT, 232068_S_AT,235286_AT, 204465_S_AT, 209906_AT, 217757_AT, 210510_S_AT, 204655_AT,1552553_A_AT, 1552798_A_AT, 237904_AT, 203888_AT, 208712_AT, 210004_AT,1555759_A_AT, 241929_AT GO: 0002376~immune 202869_AT, 205552_S_AT,206206_AT, 222838_AT, 205798_AT, 203936_S_AT, system process 220066_AT,200878_AT, 202748_AT, 201565_S_AT, 221266_S_AT, 203922_S_AT,229937_X_AT, 223502_S_AT, 215990_S_AT, 206157_AT, 201422_AT,224341_X_AT, 206637_AT, 1555756_A_AT, 209392_AT, 242907_AT, 213293_S_AT,214211_AT, 212171_X_AT, 1405_I_AT, 201566_X_AT, 221060_S_AT, 226218_AT,223501_AT, 205099_S_AT, 211661_X_AT, 210895_S_AT, 222062_AT, 204116_AT,207433_AT, 210146_X_AT, 210512_S_AT, 221463_AT, 205419_AT, 232068_S_AT,211527_X_AT, 238581_AT, 235286_AT, 209906_AT, 203140_AT, 204655_AT,210513_S_AT, 1552798_A_AT, 208978_AT, 213931_AT, 223434_AT, 210004_AT,1555759_A_AT, 219434_AT, 202638_S_AT GO: 0050896~response 210495_X_AT,229221_AT, 202869_AT, 212298_AT, 209555_S_AT, 202435_S_AT, to stimulus223560_AT, 222838_AT, 205798_AT, 1563621_AT, 202284_S_AT, 242903_AT,228490_AT, 201565_S_AT, 208922_S_AT, 229937_X_AT, 215990_S_AT,221815_AT, 205495_S_AT, 228766_AT, 201005_AT, 203060_S_AT, 201242_S_AT,242907_AT, 209122_AT, 213293_S_AT, 205128_X_AT, 214211_AT, 237252_AT,212171_X_AT, 63825_AT, 202727_S_AT, 1405_I_AT, 221060_S_AT, 201566_X_AT,211719_X_AT, 223501_AT, 205898_AT, 204058_AT, 205099_S_AT, 205566_AT,207433_AT, 210146_X_AT, 235944_AT, 217678_AT, 209047_AT, 221463_AT,232068_S_AT, 208436_S_AT, 238581_AT, 209906_AT, 1554992_AT, 243483_AT,217757_AT, 204059_S_AT, 210510_S_AT, 210513_AT, 211676_S_AT, 238669_AT,223434_AT, 225631_AT, 225097_AT, 205306_X_AT, 202638_S_AT, 201243_S_AT,201069_AT, 205552_S_AT, 227948_AT, 206206_AT, 222877_AT, 202434_S_AT,206488_S_AT, 206171_AT, 220066_AT, 200878_AT, 37145_AT, 205891_AT,203665_AT, 202436_S_AT, 207542_S_AT, 214453_S_AT, 202748_AT, 239519_AT,209921_AT, 210145_AT, 206157_AT, 223502_S_AT, 225337_AT, 220484_AT,224341_X_AT, 203887_S_AT, 206637_AT, 211138_S_AT, 1555756_A_AT,209332_AT, 209993_AT, 215813_S_AT, 212464_S_AT, 216442_X_AT, 202609_AT,226218_AT, 218934_S_AT, 211661_X_AT, 210895_S_AT, 222062_AT, 204116_AT,211026_S_AT, 210512_S_AT, 223092_AT, 202827_S_AT, 87100_AT, 205419_AT,211527_X_AT, 235286_AT, 204465_S_AT, 203140_AT, 203980_AT, 204655_AT,1552553_A_AT, 202437_S_AT, 230559_X_AT, 1552798_A_AT, 213931_AT,203888_AT, 237904_AT, 208712_AT, 210004_AT, 229797_AT, 1555759_A_AT,241929_AT, 219434_AT GO: 00322501~multicellular 219358_S_AT, 220333_AT,229221_AT, 212293_AT, 203555_S_AT, 202435_S_AT, organismal process221011_S_AT, 205798_AT, 228579_AT, 203936_S_AT, 242871_AT, 209348_S_AT,230360_AT, 202284_S_AT, 227747_AT, 1569149_AT, 201565_S_AT, 201590_X_AT,204653_AT, 204999_S_AT, 226066_AT, 215990_S_AT, 203104_AT, 200884_AT,228766_AT, 243556_AT, 201005_AT, 203060_S_AT, 210095_S_AT, 205128_X_AT,237252_AT, 214297_AT, 212171_X_AT, 221060_S_AT, 201566_X_AT, 228964_AT,223596_AT, 218502_S_AT, 206835_AT, 207433_AT, 235944_AT, 222670_S_AT,209047_AT, 232068_S_AT, 209906_AT, 1554992_AT, 243483_AT, 210510_S_AT,210513_S_AT, 206675_S_AT, 238669_AT, 204105_S_AT, 212614_AT,204881_S_AT, 225097_AT, 201069_AT, 224218_S_AT, 222877_AT, 202434_S_AT,201278_AT, 206488_S_AT, 244375_AT, 211962_S_AT, 220066_AT, 200878_AT,204141_AT, 205891_AT, 203665_AT, 202436_S_AT, 207542_S_AT, 201279_S_AT,204998_S_AT, 208816_X_AT, 239519_AT, 221266_S_AT, 233540_S_AT,210145_AT, 212190_AT, 212143_S_AT, 212086_X_AT, 220484_AT, 224341_X_AT,203887_S_AT, 1555756_A_AT, 228762_AT, 222651_S_AT, 211986_AT, 213265_AT,201324_AT, 215813_S_AT, 213503_X_AT, 204575_S_AT, 227240_AT,210427_X_AT, 202609_AT, 214724_AT, 226218_AT, 244579_AT, 218559_S_AT,211661_X_AT, 207233_S_AT, 204684_AT, 210512_S_AT, 223092_AT,202827_S_AT, 205419_AT, 204475_AT, 211527_X_AT, 204465_S_AT, 203140_AT,1560960_AT, 1569150_X_AT, 201952_AT, 203980_AT, 220935_S_AT,1552553_A_AT, 202437_S_AT, 1552798_A_AT, 208978_AT, 213931_AT,203888_AT, 208712_AT, 210757_X_AT, 222876_S_AT, 210004_AT, 229797_AT,201280_S_AT, 241929_AT, 201951_AT GO: 0050793~regulation 210495_X_AT,212298_AT, 209555_S_AT, 227948_AT, 205798_AT, 206488_S_AT, ofdevelopmental 214255_AT, 209348_S_AT, 1569149_AT, 203665_AT, 205891_AT,204998_S_AT, process 201565_S_AT, 239519_AT, 233540_S_AT, 204999_S_AT,226066_AT, 210145_AT, 215990_S_AT, 212143_S_AT, 215602_AT, 224341_X_AT,228766_AT, 210095_S_AT, 212464_S_AT, 216442_X_AT, 212171_X_AT,1553906_S_AT, 1405_I_AT, 201566_X_AT, 221060_S_AT, 211719_X_AT,226218_AT, 218559_S_AT, 207233_S_AT, 210895_S_AT, 206835_AT, 222062_AT,204116_AT, 207433_AT, 210512_S_AT, 223092_AT, 222670_S_AT, 232068_S_AT,211527_X_AT, 203140_AT, 1569150_X_AT, 220935_S_AT, 210510_S_AT,204655_AT, 210513_S_AT, 230559_X_AT, 1565754_X_AT, 1552798_A_AT,213931_AT, 1565752_AT, 208712_AT, 204105_S_AT, 1555759_A_AT, 1556423_AT,241929_AT GO: 0009897~external 229221_AT, 243483_AT, 214297_AT,201952_AT, 220307_AT, 221060_S_AT, side of plasma 1552798_A_AT,226218_AT, 205798_AT, 204105_S_AT, 210895_S_AT, 204116_AT, membrane224341_X_AT, 202756_S_AT, 1555756_A_AT, 232068_S_AT, 201951_AT,202638_S_AT GO: 0051239~regulation 212298_AT, 223660_AT, 205798_AT,206171_AT, 209348_S_AT, 220066_AT, of multicellular 200878_AT,1569149_AT, 203665_AT, 205891_AT, 204998_S_AT, 208816_X_AT, organismalprocess 201565_S_AT, 239519_AT, 201590_X_AT, 233540_S_AT, 204999_S_AT,226066_AT, 210145_AT, 215990_S_AT, 212143_S_AT, 224341_X_AT,1555756_A_AT, 215813_S_AT, 210095_S_AT, 205128_X_AT, 212171_X_AT,213503_X_AT, 1405_I_AT, 201566_X_AT, 210427_X_AT, 221060_S_AT,226218_AT, 218934_S_AT, 218559_S_AT, 207233_S_AT, 210895_S_AT,206835_AT, 222062_AT, 204116_AT, 207433_AT, 210512_S_AT, 223092_AT,222670_S_AT, 232068_S_AT, 211527_X_AT, 1554992_AT, 203140_AT,1569150_X_AT, 220935_S_AT, 210510_S_AT, 204655_AT, 210513_S_AT,1552798_A_AT, 213931_AT, 238669_AT, 237904_AT, 204105_S_AT, 208712_AT,1555759_A_AT, 1556423_AT GO: 0006952~defense 229221_AT, 216442_X_AT,210495_X_AT, 223660_AT, 1405_I_AT, 221060_S_AT, response 206206_AT,211719_X_AT, 222838_AT, 205898_AT, 205099_S_AT, 211661_X_AT, 222062_AT,206171_AT, 207433_AT, 211026_S_AT, 210146_X_AT, 208436_S_AT,232068_S_AT, 221463_AT, 220066_AT, 37145_AT, 209906_AT, 203665_AT,205891_AT, 217757_AT, 204655_AT, 1552553_A_AT, 1552798_A_AT,203922_S_AT, 206157_AT, 237904_AT, 210004_AT, 224341_X_AT, 205495_S_AT,1555756_A_AT, 1555759_A_AT, 212464_S_AT GO: 0006954~inflammatory210495_X_AT, 216442_X_AT, 229221_AT, 223660_AT, 1405_I_AT, 206206_AT,response 221060_S_AT, 211719_X_AT, 205099_S_AT, 211661_X_AT,211026_S_AT, 206171_AT, 207433_AT, 232068_S_AT, 221463_AT, 208436_S_AT,209906_AT, 203665_AT, 217757_AT, 204655_AT, 1552553_A_AT, 1552798_A_AT,203922_S_AT, 206157_AT, 237904_AT, 224341_X_AT, 210004_AT, 1555756_A_AT,1555759_A_AT, 212464_S_AT GO: 0031012~extracellular 229221_AT,216442_X_AT, 210495_X_AT, 201069_AT, 213428_S_AT, 212171_X_AT, matrix213503_X_AT, 204575_S_AT, 208816_X_AT, 229004_AT, 210513_S_AT,210427_X_AT, 201590_X_AT, 211719_X_AT, 202756_S_AT, 228873_AT,203936_S_AT, 235944_AT, 210512_S_AT, 202827_S_AT, 211527_X_AT,204475_AT, 212464_S_AT GO: 0048583~regulation 1553995_A_AT, 212171_X_AT,213503_X_AT, 227948_AT, 1405_I_AT, of response to stimulus 210427_X_AT,221060_S_AT, 226218_AT, 223501_AT, 205798_AT, 210895_S_AT, 222062_AT,207433_AT, 210512_S_AT, 220066_AT, 232068_S_AT, 208436_S_AT,211527_X_AT, 203939_AT, 209906_AT, 203665_AT, 205891_AT, 203140_AT,217757_AT, 203980_AT, 208816_X_AT, 204655_AT, 210513_S_AT, 230559_X_AT,201590_X_AT, 1552798_A_AT, 210145_AT, 223502_S_AT, 215990_S_AT,224341_X_AT, 225097_AT, 1555756_A_AT, 1555759_A_AT, 202638_S_AT GO:0005578~proteinaceous 216442_X_AT, 210495_X_AT, 201069_AT, 213428_S_AT,212171_X_AT, extracellular matrix 213503_X_AT, 204575_S_AT, 208816_X_AT,229004_AT, 210513_S_AT, 210427_X_AT, 201590_X_AT, 211719_X_AT,202756_S_AT, 228873_AT, 203936_S_AT, 235944_AT, 210512_S_AT,202827_S_AT, 211527_X_AT, 204475_AT, 212464_S_AT GO: 0009986~cellsurface 229221_AT, 214297_AT, 212171_X_AT, 209555_S_AT, 221060_S_AT,226218_AT, 205798_AT, 206488_S_AT, 210895_S_AT, 204116_AT, 210512_S_AT,220066_AT, 232068_S_AT, 211527_X_AT, 243483_AT, 201952_AT, 220307_AT,210513_S_AT, 221266_S_AT, 1552798_A_AT, 204105_S_AT, 224341_X_AT,202756_S_AT, 228766_AT, 1555756_A_AT, 241929_AT, 209993_AT, 201951_AT,202638_S_AT GO: 0002682~regulation 229221_AT, 212171_X_AT, 1405_I_AT,201566_X_AT, 221060_S_AT, 226218_AT, of immune system 223501_AT,218559_S_AT, 205798_AT, 207233_S_AT, 210895_S_AT, 222062_AT, process204116_AT, 207433_AT, 210512_S_AT, 202284_S_AT, 222670_S_AT, 220066_AT,232068_S_AT, 211527_X_AT, 209906_AT, 203665_AT, 205891_AT, 203140_AT,217757_AT, 204655_AT, 210513_S_AT, 201565_S_AT, 1552798_A_AT, 226066_AT,223502_S_AT, 213931_AT, 215990_S_AT, 224341_X_AT, 1555756_A_AT,1555759_A_AT, 202638_S_AT GO: 0005615~extracellular 237252_AT,210495_X_AT, 216442_X_AT, 201069_AT, 212171_X_AT, 1405_I_AT, space211719_X_AT, 223501_AT, 229900_AT, 207433_AT, 227265_AT, 203936_S_AT,210512_S_AT, 226545_AT, 221463_AT, 211527_X_AT, 235286_AT, 37145_AT,203665_AT, 217757_AT, 204655_AT, 210513_S_AT, 212190_AT, 223502_S_AT,212143_S_AT, 203888_AT, 203887_S_AT, 202756_S_AT, 205495_S_AT,204834_AT, 1555759_A_AT, 1556423_AT, 210095_S_AT, 202638_S_AT,212464_S_AT GO: 0048731~system 219358_S_AT, 229221_AT, 201069_AT,212298_AT, 224218_S_AT, 222877_AT, development 205798_AT, 244375_AT,211962_S_AT, 209348_S_AT, 203936_S_AT, 202284_S_AT, 230360_AT,200878_AT, 204141_AT, 1569149_AT, 203665_AT, 204998_S_AT, 206816_X_AT,201565_S_AT, 239519_AT, 201590_X_AT, 221266_S_AT, 233540_S_AT,204999_S_AT, 204653_AT, 210145_AT, 226066_AT, 212190_AT, 215990_S_AT,212143_S_AT, 212086_X_AT, 220484_AT, 200884_AT, 228762_AT, 243556_AT,203060_S_AT, 201005_AT, 222651_S_AT, 211986_AT, 210095_S_AT, 201324_AT,213503_X_AT, 214297_AT, 212171_X_AT, 204575_S_AT, 227240_AT,201566_X_AT, 210427_X_AT, 228964_AT, 226218_AT, 244579_AT, 218559_S_AT,207233_S_AT, 206835_AT, 218502_S_AT, 204684_AT, 207433_AT, 202827_S_AT,223092_AT, 222670_S_AT, 210512_S_AT, 205419_AT, 211527_X_AT,204465_S_AT, 1554992_AT, 203140_AT, 1560960_AT, 1569150_X_AT, 201952_AT,220935_S_AT, 210510_S_AT, 210513_S_AT, 208978_AT, 213931_AT,204105_S_AT, 208712_AT, 212614_AT, 204881_S_AT, 222876_S_AT, 229797_AT,201951_AT GO: 0051707~response 237252_AT, 1405_I_AT, 202727_S_AT,221060_S_AT, 211661_X_AT, 222062_AT, to other organism 207433_AT,232068_S_AT, 220066_AT, 208436_S_AT, 242903_AT, 37145_AT, 214453_S_AT,204655_AT, 1552553_A_AT, 1552798_A_AT, 211676_S_AT, 229937_X_AT,210145_AT, 206157_AT, 203888_AT, 224341_X_AT, 203887_S_AT, 205495_S_AT,1555756_A_AT, 1555759_A_AT, 213293_S_AT GO: 0007275~multicellular220333_AT, 219358_S_AT, 229221_AT, 201069_AT, 212298_AT, 224218_S_AT,organismal 221011_S_AT, 222877_AT, 201278_AT, 205798_AT, 244375_AT,211962_S_AT, development 209348_S_AT, 242871_AT, 203936_S_AT,202284_S_AT, 230360_AT, 200878_AT, 204141_AT, 1569149_AT, 203665_AT,201279_S_AT, 204998_S_AT, 206816_X_AT, 201565_S_AT, 239519_AT,201590_X_AT, 221266_S_AT, 233540_S_AT, 204999_S_AT, 204653_AT,210145_AT, 226066_AT, 212190_AT, 215990_S_AT, 212143_S_AT, 203104_AT,212086_X_AT, 220484_AT, 200884_AT, 203887_S_AT, 228762_AT, 243556_AT,203060_S_AT, 201005_AT, 222651_S_AT, 211986_AT, 210095_S_AT, 201324_AT,237252_AT, 212171_X_AT, 213503_X_AT, 214297_AT, 204575_S_AT, 227240_AT,201566_X_AT, 210427_X_AT, 228964_AT, 214724_AT, 226218_AT, 244579_AT,218559_S_AT, 207233_S_AT, 206835_AT, 218502_S_AT, 204684_AT, 207433_AT,202827_S_AT, 223092_AT, 210512_S_AT, 222670_S_AT, 205419_AT,211527_X_AT, 204465_S_AT, 1554992_AT, 203140_AT, 1560960_AT,1569150_X_AT, 201952_AT, 220935_S_AT, 210510_S_AT, 210513_S_AT,208978_AT, 206675_S_AT, 213931_AT, 203888_AT, 204105_S_AT, 208712_AT,212614_AT, 204881_S_AT, 210757_X_AT, 222876_S_AT, 225097_AT, 229797_AT,201280_S_AT, 201951_AT GO: 0032101~regulation 1553995_A_AT, 205891_AT,203140_AT, 212171_X_AT, 213503_X_AT, 217757_AT, of response to external203980_AT, 208816_X_AT, 1405_I_AT, 204655_AT, 210513_S_AT, 221060_S_AT,stimulus 210427_X_AT, 201590_X_AT, 1552798_A_AT, 210145_AT, 215990_S_AT,224341_X_AT, 207433_AT, 210512_S_AT, 1555759_A_AT, 232068_S_AT,211527_X_AT, 203939_AT GO: 0022610~biological 229221_AT, 210495_X_AT,216442_X_AT, 212298_AT, 209555_S_AT, 1405_I_AT, adhesion 211719_X_AT,222838_AT, 210360_S_AT, 222877_AT, 211066_X_AT, 205898_AT, 205099_S_AT,206488_S_AT, 215836_S_AT, 225188_AT, 228640_AT, 227747_AT, 213428_S_AT,201952_AT, 204655_AT, 210510_S_AT, 225189_S_AT, 239519_AT, 203037_S_AT,205718_AT, 216250_S_AT, 204105_S_AT, 210004_AT, 228766_AT, 1555756_A_AT,228873_AT, 1555759_A_AT, 241929_AT, 201125_S_AT, 201005_AT, 201951_AT,202638_S_AT, 212464_S_AT GO: 0007155~cell 229221_AT, 210495_X_AT,216442_X_AT, 212298_AT, 209555_S_AT, 1405_I_AT, adhesion 211719_X_AT,222838_AT, 210360_S_AT, 222877_AT, 211066_X_AT, 205898_AT, 205099_S_AT,206488_S_AT, 215836_S_AT, 225188_AT, 228640_AT, 227747_AT, 213428_S_AT,201952_AT, 204655_AT, 210510_S_AT, 225189_S_AT, 239519_AT, 203037_S_AT,205718_AT, 216250_S_AT, 204105_S_AT, 210004_AT, 228766_AT, 1555756_A_AT,228873_AT, 1555759_A_AT, 241929_AT, 201125_S_AT, 201005_AT, 201951_AT,202638_S_AT, 212464_S_AT GO: 0048856~anatomical 219358_S_AT,210495_X_AT, 229221_AT, 201069_AT, 212238_AT, 224218_S_AT, structuredevelopment 222877_AT, 201278_AT, 205798_AT, 244375_AT, 211962_S_AT,209348_S_AT, 203936_S_AT, 202284_S_AT, 230360_AT, 200878_AT, 204141_AT,1569149_AT, 203665_AT, 201279_S_AT, 204998_S_AT, 208816_X_AT,201565_S_AT, 239519_AT, 201590_X_AT, 221266_S_AT, 233540_S_AT,204999_S_AT, 204653_AT, 210145_AT, 226066_AT, 212190_AT, 215990_S_AT,212143_S_AT, 212086_X_AT, 220484_AT, 200884_AT, 228762_AT, 243556_AT,203060_S_AT, 201005_AT, 222651_S_AT, 211986_AT, 210095_S_AT, 201324_AT,212464_S_AT, 216442_X_AT, 213503_X_AT, 214297_AT, 212171_X_AT,204575_S_AT, 227240_AT, 201566_X_AT, 210427_X_AT, 228964_AT,211719_X_AT, 226218_AT, 244579_AT, 218559_S_AT, 207233_S_AT, 206835_AT,218502_S_AT, 204684_AT, 207433_AT, 202827_S_AT, 223092_AT, 222670_S_AT,210512_S_AT, 205419_AT, 211527_X_AT, 204465_S_AT, 1554992_AT, 203140_AT,1560960_AT, 1569150_X_AT, 201952_AT, 220935_S_AT, 210510_S_AT,210513_S_AT, 208978_AT, 213931_AT, 204105_S_AT, 208712_AT, 212614_AT,204881_S_AT, 210757_X_AT, 222876_S_AT, 229797_AT, 201280_S_AT, 201951_ATGO: 0065008~regulation 223723_AT, 210495_X_AT, 212298_AT, 209555_S_AT,202435_S_AT, 227948_AT, of biological quality 205798_AT, 201278_AT,202434_S_AT, 206488_S_AT, 214255_AT, 202284_S_AT, 200878_AT, 203665_AT,205891_AT, 202436_S_AT, 201279_S_AT, 208816_X_AT, 201565_S_AT,239519_AT, 201590_X_AT, 210145_AT, 223502_S_AT, 215990_S_AT, 200884_AT,215602_AT, 203887_S_AT, 224341_X_AT, 201422_AT, 228766_AT, 203060_S_AT,201005_AT, 215813_S_AT, 201324_AT, 205128_X_AT, 212464_S_AT, 214211_AT,237252_AT, 216442_X_AT, 212171_X_AT, 213503_X_AT, 1553906_S_AT,1405_I_AT, 221060_S_AT, 201566_X_AT, 210427_X_AT, 211719_X_AT,223596_AT, 226218_AT, 223501_AT, 34210_AT, 204661_AT, 205099_S_AT,206835_AT, 207433_AT, 235944_AT, 210512_S_AT, 208436_S_AT, 232068_S_AT,211527_X_AT, 209906_AT, 1554992_AT, 203140_AT, 243483_AT, 203980_AT,204655_AT, 210510_S_AT, 210513_S_AT, 202437_S_AT, 230559_X_AT,1565754_X_AT, 1552738_A_AT, 213931_AT, 203888_AT, 238669_AT, 1565752_AT,210757_X_AT, 1555759_A_AT, 241929_AT, 201280_S_AT, 223394_AT GO:0007166~cell surface 212298_AT, 223660_AT, 210360_S_AT, 242794_AT,205798_AT, 244375_AT, receptor linked signal 206171_AT, 232333_AT,218589_AT, 205891_AT, 207610_S_AT, 239519_AT, transduction 234645_AT,226066_AT, 203104_AT, 212977_AT, 223939_AT, 206637_AT, 1555756_A_AT,209392_AT, 212171_X_AT, 1405_I_AT, 235457_AT, 202609_AT, 214724_AT,226218_AT, 205838_AT, 205099_S_AT, 211661_X_AT, 207233_S_AT, 222062_AT,232746_AT, 210146_X_AT, 210512_S_AT, 205419_AT, 211527_X_AT, 244414_AT,209906_AT, 242405_AT, 210510_S_AT, 204655_AT, 210513_S_AT, 214054_AT,203037_S_AT, 210264_AT, 205718_AT, 237904_AT, 208712_AT, 212614_AT,210258_AT, 206134_AT, 225097_AT, 1555759_A_AT, 201125_S_AT GO:0050727~regulation 1553995_A_AT, 203140_AT, 205891_AT, 217757_AT,203980_AT, 1405_I_AT, of inflammatory 204655_AT, 221060_S_AT,1552798_A_AT, 210145_AT, 215990_S_AT, response 224341_X_AT, 207433_AT,1555759_A_AT, 232068_S_AT, 203939_AT GO: 0006950~response 210495_X_AT,229221_AT, 201069_AT, 212298_AT, 209555_S_AT, 227948_AT, to stress223660_AT, 206206_AT, 222838_AT, 206488_S_AT, 206171_AT, 202284_S_AT,1563621_AT, 220066_AT, 200878_AT, 37145_AT, 228490_AT, 203665_AT,205891_AT, 239519_AT, 203922_S_AT, 210145_AT, 215990_S_AT, 221815_AT,206157_AT, 225337_AT, 224341_X_AT, 203887_S_AT, 205495_S_AT, 228766_AT,211138_S_AT, 1555756_A_AT, 201005_AT, 203060_S_AT, 201242_S_AT,215813_S_AT, 212464_S_AT, 205128_X_AT, 237252_AT, 216442_X_AT,212171_X_AT, 63825_AT, 1405_I_AT, 221060_S_AT, 211719_X_AT, 218934_S_AT,205898_AT, 205099_S_AT, 211661_X_AT, 205566_AT, 222062_AT, 211026_S_AT,207433_AT, 210146_X_AT, 235944_AT, 202827_S_AT, 210512_S_AT, 221463_AT,87100_AT, 232068_S_AT, 208436_S_AT, 211527_X_AT, 204465_S_AT, 209906_AT,203140_AT, 243483_AT, 217757_AT, 210510_S_AT, 204655_AT, 1552553_A_AT,230559_X_AT, 210513_S_AT, 1552798_A_AT, 238669_AT, 203888_AT, 237904_AT,208712_AT, 210004_AT, 225631_AT, 225097_AT, 205306_X_AT, 1555759_A_AT,241929_AT, 201243_S_AT GO: 0032502~developmental 219358_S_AT, 220333_AT,229221_AT, 210495_X_AT, 212298_AT, 221011_S_AT, process 205798_AT,203936_S_AT, 242871_AT, 209348_S_AT, 230360_AT, 202284_S_AT, 1569149_AT,201565_S_AT, 201590_X_AT, 204653_AT, 204999_S_AT, 226066_AT,215990_S_AT, 203104_AT, 200884_AT, 243556_AT, 201005_AT, 203060_S_AT,210095_S_AT, 205128_X_AT, 237252_AT, 214297_AT, 212171_X_AT, 1405_I_AT,201566_X_AT, 211719_X_AT, 228964_AT, 218502_S_AT, 206835_AT, 207433_AT,222670_S_AT, 1554992_AT, 210510_S_AT, 210513_S_AT, 206675_S_AT,238669_AT, 212614_AT, 204105_S_AT, 204881_S_AT, 225097_AT, 201069_AT,224218_S_AT, 222877_AT, 201278_AT, 244375_AT, 211962_S_AT, 200878_AT,204141_AT, 203665_AT, 201279_S_AT, 204998_S_AT, 208816_X_AT, 239519_AT,221266_S_AT, 233540_S_AT, 212190_AT, 210145_AT, 212143_S_AT,212086_X_AT, 220484_AT, 203887_S_AT, 228762_AT, 222651_S_AT, 211986_AT,201324_AT, 215813_S_AT, 212464_S_AT, 216442_X_AT, 213503_X_AT,204575_S_AT, 227240_AT, 210427_X_AT, 214724_AT, 226218_AT, 244579_AT,218559_S_AT, 207233_S_AT, 204684_AT, 210512_S_AT, 223092_AT,202827_S_AT, 205419_AT, 211527_X_AT, 204465_S_AT, 203140_AT, 1560960_AT,1569150_X_AT, 201952_AT, 203980_AT, 220935_S_AT, 204655_AT, 208978_AT,213931_AT, 203888_AT, 208712_AT, 222876_S_AT, 210757_X_AT, 229797_AT,1555759_A_AT, 201280_S_AT, 201951_AT GO: 0031347~regulation1553995_A_AT, 205891_AT, 203140_AT, 217757_AT, 203980_AT, 1405_I_AT, ofdefense response 204655_AT, 221060_S_AT, 1552798_A_AT, 210145_AT,215990_S_AT, 224341_X_AT, 207433_AT, 1555756_A_AT, 1555759_A_AT,232068_S_AT, 208436_S_AT, 220066_AT, 203939_AT GO: 0009607~response237252_AT, 1405_I_AT, 202727_S_AT, 221060_S_AT, 218934_S_AT,211661_X_AT, to biotic stimulus 222062_AT, 207433_AT, 232068_S_AT,220066_AT, 208436_S_AT, 242903_AT, 37145_AT, 214453_S_AT, 204655_AT,1552553_A_AT, 211676_S_AT, 1552798_A_AT, 229937_X_AT, 210145_AT,20615_AT, 203888_AT, 208712_AT, 224341_X_AT, 203887_S_AT, 205495_S_AT,1555756_A_AT, 1555759_A_AT, 213293_S_AT GO: 0019955~cytokine 204912_AT,209555_S_AT, 217757_AT, 202727_S_AT, 226218_AT, 211676_S_AT, binding205898_S_AT, 205099_S_AT, 205798_AT, 203104_AT, 206488_S_AT, 222062_AT,204116_AT, 228766_AT, 241929_AT, 242903_AT GO: 0050776~regulation209906_AT, 203665_AT, 205891_AT, 203140_AT, 217757_AT, 221060_S_AT, ofimmune response 1552798_A_AT, 226218_AT, 223501_AT, 223502_S_AT,215590_S_AT, 205798_AT, 210895_S_AT, 222062_AT, 224341_X_AT, 207433_AT,1555756_A_AT, 220066_AT, 232068_S_AT, 202638_S_AT GO: 0040011~locomotion210495_X_AT, 216442_X_AT, 229221_AT, 212298_AT, 1405_I_AT, 211719_X_AT,222877_AT, 205898_AT, 204268_AT, 205099_S_AT, 211661_X_AT, 207433_AT,202827_S_AT, 221463_AT, 235286_AT, 209906_AT, 1560960_AT, 204655_AT,210510_S_AT, 239519_AT, 212614_AT, 204105_S_AT, 1555759_A_AT, 209392_AT,202638_S_AT, 212464_S_AT GO: 0080134~regulation 1553995_A_AT,213503_X_AT, 227948_AT, 1405_I_AT, 210427_X_AT, of response to stress221060_S_AT, 207433_AT, 220066_AT, 232068_S_AT, 208436_S_AT, 203939_AT,203140_AT, 205891_AT, 217757_AT, 203980_AT, 208816_X_AT, 204655_AT,230559_X_AT, 201590_X_AT, 1552798_A_AT, 210145_AT, 215990_S_AT,224341_X_AT, 225097_AT, 155575_A_AT, 1555759_A_AT GO: 0007626~locomotory209906_AT, 1405_I_AT, 204655_AT, 202609_AT, 222877_AT, 205898_AT,behavior 205099_S_AT, 211661_X_AT, 220484_AT, 225097_AT, 207433_AT,229797_AT, 223092_AT, 1555759_A_AT, 209392_AT, 221463_AT, 235286_AT GO:0002684~positive 209906_AT, 205891_AT, 203140_AT, 212171_X_AT,210513_S_AT, 221060_S_AT, regulation of immune 226218_AT, 1552798_A_AT,223501_AT, 223502_S_AT, 215990_S_AT, 205798_AT, system process210895_S_AT, 222062_AT, 204116_AT, 224341_X_AT, 1555756_A_AT,210512_S_AT, 202284_S_AT, 220066_AT, 232068_S_AT, 211527_X_AT,202638_S_AT GO: 0000267~cell 1553995_A_AT, 202869_AT, 209555_S_AT,202435_S_AT, 205552_S_AT, fraction 227134_AT, 211066_X_AT, 222877_AT,219412_AT, 202434_S_AT, 206488_S_AT, 208789_AT, 203939_AT, 203665_AT,202436_S_AT, 216080_S_AT, 201590_X_AT, 208161_S_AT, 210145_AT,223502_S_AT, 236345_AT, 1557938_S_AT, 212086_X_AT, 228766_AT, 209993_AT,201324_AT, 215813_S_AT, 205128_X_AT, 213503_X_AT, 1405_I_AT,210427_X_AT, 202609_AT, 223596_AT, 223501_AT, 204058_AT, 34210_AT,204461_AT, 218613_AT, 210146_X_AT, 215836_S_AT, 1554992_AT, 204059_S_AT,203980_AT, 204655_AT, 202437_S_AT, 238669_AT, 204257_AT, 204811_S_AT,210004_AT, 202087_S_AT, 1555759_A_AT, 241929_AT, 203355_S_AT GO:0045028~purinergic 218589_AT, 205891_AT, 223939_AT, 206637_AT,223660_AT, 206171_AT, nudeotide receptor 205419_AT, 237904_AT activity,G-protein coupled GO: 0001608~nucleotide 218589_AT, 205891_AT,223939_AT, 206637_AT, 223660_AT, 206171_AT, receptor activity, G-205419_AT, 237904_AT protein coupled GO: 0004930~G-protein 218589_AT,209906_AT, 205891_AT, 207610_S_AT, 223660_AT, 210264_AT, coupledreceptor activity 205898_AT, 205099_S_AT, 211661_X_AT, 237904_AT,212977_AT, 232746_AT, 223939_AT, 206637_AT, 206171_AT, 205419_AT GO:0016502~nucleotide 218589_AT, 205891_AT, 223939_AT, 206637_AT,223660_AT, 206171_AT, receptor activity 205419_AT, 237904_AT GO:0001614~purinergic 218589_AT, 205891_AT, 223939_AT, 206637_AT,223660_AT, 206171_AT, nucleotide receptor 205419_AT, 237904_AT GO:0005626~insoluble 1553995_A_AT, 202869_AT, 209555_S_AT, 205552_S_AT,202435_S_AT, friction 202609_AT, 223596_AT, 222877_AT, 227134_AT,211066_X_AT, 204661_AT, 34210_AT, 219412_AT, 202434_S_AT, 218613_AT,206488_S_AT, 210146_X_AT, 215836_S_AT, 208789_AT, 203939_AT, 1554992_AT,203665_AT, 202436_S_AT, 202437_S_AT, 216080_S_AT, 208161_S_AT,210145_AT, 1557938_S_AT, 236345_AT, 238669_AT, 204257_AT, 212086_X_AT,204881_S_AT, 210004_AT, 228766_AT, 241929_AT, 203355_S_AT, 209993_AT,215813_S_AT, 201324_AT, 205128_X_AT GO: 0048513~organ 219358_S_AT,229221_AT, 201069_AT, 212298_AT, 222877_AT, 205798_AT, development244375_AT, 211962_S_AT, 203936_S_AT, 209348_S_AT, 202284_S_AT,200878_AT, 203665_AT, 208816_K_AT, 239519_AT, 201565_S_AT, 201590_X_AT,221266_S_AT, 233540_S_AT, 204653_AT, 226066_AT, 210145_AT, 215990_S_AT,212086_X_AT, 220484_AT, 200884_AT, 228762_AT, 201324_AT, 213503_X_AT,214297_AT, 212171_X_AT, 204575_S_AT, 210427_X_AT, 201566_X_AT,228964_AT, 226218_AT, 218559_S_AT, 207233_S_AT, 206835_AT, 207433_AT,210512_S_AT, 202827_S_AT, 222670_S_AT, 205419_AT, 211527_X_AT,204465_S_AT, 203140_AT, 1560960_AT, 220935_S_AT, 210510_S_AT,210513_S_AT, 208978_AT, 213931_AT, 208712_AT, 212614_AT, 204881_S_AT,222876_S_AT, 229797_AT GO: 0002697~regulation 205798_AT, 203665_AT,205891_AT, 203140_AT, 222062_AT, 217757_AT, of immune effector207433_AT, 220066_AT, 226218_AT, 202638_S_AT, 215990_S_AT process GO:0051384~response 208712_AT, 217757_AT, 203980_AT, 207433_AT, 204655_AT,1405_I_AT, to glucocorticoid 202284_S_AT, 1555759_A_AT, 215813_S_AT,210145_AT, 205128_X_AT, stimulus 238669_AT GO: 0005624~membrane1553995_A_AT, 202869_AT, 209555_S_AT, 205552_S_AT, 202435_S_AT, fraction202609_AT, 223596_AT, 222877_AT, 227134_AT, 211066_X_AT, 204661_AT,34210_AT, 219412_AT, 202434_S_AT, 218613_AT, 206488_S_AT, 210146_X_AT,215836_S_AT, 208789_AT, 203939_AT, 1554992_AT, 203665_AT, 202436_S_AT,202437_S_AT, 216080_S_AT, 208161_S_AT, 210145_AT, 1557938_S_AT,236345_AT, 238669_AT, 204257_AT, 204881_S_AT, 210004_AT, 228766_AT,241929_AT, 203355_S_AT, 209993_AT, 215813_S_AT, 201324_AT, 205128_X_AThsa04060:Cytokine- 214581_X_AT, 204912_AT, 212171_X_AT, 202727_S_AT,1405_I_AT, 204655_AT, cytokine receptor 210513_S_AT, 211676_S_AT,226218_AT, 223501_AT, 218856_AT, 205898_AT, interaction 223502_S_AT,205099_S_AT, 203104_AT, 205798_AT, 204116_AT, 207433_AT, 210512_S_AT,1555759_A_AT, 221463_AT, 211527_X_AT, 242903_AT GO: 0031349~positive205891_AT, 203980_AT, 1405_I_AT, 204655_AT, 221060_S_AT, 1552798_A_AT,regulation of defense 210145_AT, 224341_X_AT, 1555756_A_AT,1555759_A_AT, 232068_S_AT, response 208436_S_AT, 220066_AT GO:0048584~positive 209906_AT, 205891_AT, 212171_X_AT, 203980_AT,1405_I_AT, 204655_AT, regulation of response to 210513_S_AT,221060_S_AT, 1552798_A_AT, 223501_AT, 210145_AT, stimulus 223502_S_AT,222062_AT, 224341_X_AT, 225097_AT, 1555756_A_AT, 210512_S_AT,1555759_A_AT, 220066_AT, 232068_S_AT, 208436_S_AT, 211527_X_AT GO:0031960~response 208712_AT, 217757_AT, 203980_AT, 207433_AT, 204655_AT,1405_I_AT, to corticosteroid 202284_S_AT, 1555759_A_AT, 215813_S_AT,210145_AT, 205128_X_AT, stimulus 238669_AT GO: 0042221~response229221_AT, 201069_AT, 202435_S_AT, 222877_AT, 202434_S_AT, 202284_S_AT,to chemical stimulus 220066_AT, 200878_AT, 203665_AT, 207542_S_AT,202436_S_AT, 201565_S_AT, 209921_AT, 210145_AT, 224341_X_AT,203887_S_AT, 1555756_A_AT, 209392_AT, 201242_S_AT, 209993_AT,215813_S_AT, 209122_AT, 205128_X_AT, 237252_AT, 212171_X_AT, 1405_I_AT,201566_X_AT, 221060_S_AT, 202609_AT, 218934_S_AT, 204058_AT, 205898_AT,205099_S_AT, 211661_X_AT, 207433_AT, 217678_AT, 210512_S_AT,202827_S_AT, 209047_AT, 221463_AT, 232068_S_AT, 211527_X_AT, 235286_AT,209906_AT, 217757_AT, 204059_S_AT, 203980_AT, 204655_AT, 210513_S_AT,202437_S_AT, 1552798_A_AT, 213931_AT, 238669_AT, 203888_AT, 208712_AT,210004_AT, 1555759_A_AT, 201243_S_AT GO: 0065007~biological 213891_S_AT,1553995_A_AT, 223723_AT, 212298_AT, 223660_AT, 222838_AT, regulation219412_AT, 205798_AT, 205960_AT, 209348_S_AT, 217997_AT, 232333_AT,225171_AT, 220307_AT, 201565_S_AT, 201590_X_AT, 230266_AT, 209684_AT,204999_S_AT, 204653_AT, 226066_AT, 215990_S_AT, 221815_AT, 203104_AT,200884_AT, 204834_AT, 222146_S_AT, 228766_AT, 210095_S_AT, 205128_X_AT,214211_AT, 1560485_AT, 214581_X_AT, 63825_AT, 1405_I_AT, 201566_X_AT,228964_AT, 211719_X_AT, 223501_AT, 212387_AT, 205898_AT, 205099_S_AT,218502_S_AT, 206835_AT, 207433_AT, 235944_AT, 222670_S_AT, 212382_AT,1554992_AT, 217757_AT, 1545754_X_AT, 209606_AT, 211676_S_AT,206675_S_AT, 225842_AT, 216250_S_AT, 238669_AT, 1565752_AT, 204105_S_AT,206134_AT, 202638_S_AT, 227948_AT, 242794_AT, 202434_S_AT, 222858_S_AT,206488_S_AT, 211962_S_AT, 225173_AT, 208789_AT, 220066_AT, 200878_AT,225166_AT, 203665_AT, 205891_AT, 208816_X_AT, 239519_AT, 233540_S_AT,218856_AT, 210145_AT, 212190_AT, 223502_S_AT, 212143_S_AT, 1557938_S_AT,215602_AT, 223939_AT, 203887_S_AT, 206637_AT, 1555756_A_AT, 222651_S_AT,215813_S_AT, 218501_AT, 227240_AT, 210427_X_AT, 226218_AT, 218934_S_AT,244579_AT, 204661_AT, 207233_S_AT, 210895_S_AT, 222062_AT, 232746_AT,227265_AT, 210512_S_AT, 225188_AT, 211527_X_AT, 244414_AT, 203140_AT,242405_AT, 1569150_X_AT, 201952_AT, 203980_AT, 225189_S_AT, 230559_X_AT,210264_AT, 213931_AT, 210258_AT, 222876_S_AT, 210757_X_AT, 201280_S_AT,201951_AT, 219358_S_AT, 210495_X_AT, 229221_AT, 209555_S_AT,202435_S_AT, 221011_S_AT, 210360_S_AT, 217999_S_AT, 224480_S_AT,203936_S_AT, 228057_AT, 214255_AT, 202284_S_AT, 242903_AT, 1569149_AT,228490_AT, 207610_S_AT, 209568_S_AT, 203753_AT, 1553982_A_AT, 212977_AT,201422_AT, 230925_AT, 243556_AT, 201005_AT, 203060_S_AT, 213293_S_AT,237252_AT, 212171_X_AT, 214297_AT, 202727_S_AT, 235457_AT, 221060_S_AT,223596_AT, 34210_AT, 223398_AT, 205566_AT, 218613_AT, 221463_AT,232068_S_AT, 208436_S_AT, 209906_AT, 243483_AT, 210510_S_AT,210513_S_AT, 212614_AT, 212386_AT, 225097_AT, 219994_AT, 1556423_AT,203355_S_AT, 224218_S_AT, 201278_AT, 206171_AT, 1560228_AT, 237442_AT,203939_AT, 218589_AT, 202436_S_AT, 201279_S_AT, 204998_S_AT, 234645_AT,206157_AT, 225337_AT, 224341_X_AT, 209392_AT, 229435_AT, 201324_AT,205681_AT, 212464_S_AT, 216442_X_AT, 213503_X_AT, 1553906_S_AT,228708_AT, 202609_AT, 218559_S_AT, 211661_X_AT, 214841_AT, 204116_AT,225207_AT, 202827_S_AT, 223092_AT, 205419_AT, 87100_AT, 228368_AT,220935_S_AT, 204655_AT, 1552553_A_AT, 202437_S_AT, 203037_S_AT,214054_AT, 1552798_A_AT, 208978_AT, 203888_AT, 237904_AT, 208712_AT,1555759_A_AT, 241929_AT, 242157_AT, 219434_AT, 223394_AT GO:0050865~regulation 203665_AT, 203140_AT, 205891_AT, 221060_S_AT,1552798_A_AT, 226218_AT, of cell activation 223501_AT, 223502_S_AT,215990_S_AT, 205798_AT, 210895_S_AT, 222062_AT, 224341_X_AT, 204116_AT,207433_AT, 202284_S_AT, 232068_S_AT GO: 0048545~response 203665_AT,207542_S_AT, 203980_AT, 217757_AT, 1405_I_AT, 204655_AT, to steroidhormone 210145_AT, 238669_AT, 208712_AT, 207433_AT, 1555759_A_AT,202827_S_AT, stimulus 202284_S_AT, 209047_AT, 215813_S_AT, 205128_X_ATGO: 0006935~chemotaxis 209906_AT, 207433_AT, 204655_AT, 1405_I_AT,1555759_A_AT, 209392_AT, 221463_AT, 222877_AT, 235286_AT, 205898_AT,205099_S_AT, 211661_X_AT GO: 0042330~taxis 209906_AT, 207433_AT,204655_AT, 1405_I_AT, 1555759_A_AT, 209392_AT, 221463_AT, 222877_AT,235286_AT, 205898_AT, 205099_S_AT, 211661_X_AT GO: 0002703~regulation205798_AT, 203665_AT, 205891_AT, 203140_AT, 222062_AT, 207433_AT, ofleukocyte mediated 220066_AT, 226218_AT, 215990_S_AT immunity GO:0002822~regulation 205798_AT, 203140_AT, 210895_S_AT, 222062_AT,207433_AT, 220066_AT, of adaptive immune 226218_AT, 223501_AT,223502_S_AT, 215990_S_AT response based on somatic recombination ofimmune receptors built from immunoglobulin superfamily domains G0:0001568~blood 229221_AT, 203665_AT, 201069_AT, 214297_AT, 212298_AT,213503_X_AT, vessel development 212171_X_AT, 204575_S_AT, 208816_X_AT,210510_S_AT, 239519_AT, 210427_X_AT, 210513_S_AT, 201590_X_AT,222877_AT, 211962_S_AT, 202827_S_AT, 210512_S_AT, 211527_X_AT, 200878_ATG0: 0030154~cell 220333_AT, 210495_X_AT, 229221_AT, 212298_AT,222877_AT, 205798_AT, differentiation 201278_AT, 211962_S_AT, 242871_AT,203936_S_AT, 209348_S_AT, 230360_AT, 204141_AT, 200878_AT, 1569149_AT,201279_S_AT, 204998_S_AT, 239519_AT, 201565_S_AT, 221266_S_AT,233540_S_AT, 204999_S_AT, 226066_AT, 212190_AT, 215990_S_AT,212143_S_AT, 220484_AT, 243556_AT, 210095_S_AT, 201324_AT, 212464_S_AT,216442_X_AT, 212171_X_AT, 214297_AT, 204575_S_AT, 227240_AT,201566_X_AT, 211719_X_AT, 228964_AT, 226218_AT, 207233_S_AT, 207433_AT,210512_S_AT, 202827_S_AT, 205419_AT, 211527_X_AT, 204465_S_AT,1554992_AT, 203140_AT, 1560960_AT, 201952_AT, 1569150_X_AT, 203980_AT,220935_S_AT, 210510_S_AT, 210513_S_AT, 213931_AT, 204105_S_AT,208712_AT, 210757_X_AT, 229797_AT, 201280_S_AT, 201951_AT GO:0001944~vasculature 229221_AT, 203665_AT, 201069_AT, 214297_AT,212298_AT, 213503_X_AT, development 212171_X_AT, 204575_S_AT,208816_X_AT, 210510_S_AT, 239519_AT, 210427_X_AT, 210513_S_AT,201590_X_AT, 222877_AT, 211962_S_AT, 202827_S_AT, 210512_S_AT,211527_X_AT, 200878_AT G0: 0002819~regulation 205798_AT, 203140_AT,210895_S_AT, 222062_AT, 207433_AT, 220066_AT, of adaptive immune226218_AT, 223501_AT, 223502_S_AT, 215990_S_AT response GO:0051241~negative 203665_AT, 203140_AT, 205891_AT, 213503_X_AT,212171_X_AT, 208816_X_AT, regulation of 210427_X_AT, 210513_S_AT,2101590_X_AT, 215990_S_AT, 206835_AT, 207433_AT, multicellularorganismal 210512_S_AT, 220066_AT, 211527_X_AT GO: 0051704~multi-237252_AT, 202727_S_AT, 1405_I_AT, 221060_S_AT, 205898_AT, 211661_X_AT,organism process 210895_S_AT, 222062_AT, 204116_AT, 232746_AT,207433_AT, 208436_S_AT, 220066_AT, 232068_S_AT, 204475_AT, 242903_AT,37145_AT, 214453_S_AT, 204655_AT, 1552553_A_AT, 211676_S_AT,1552798_A_AT, 229937_X_AT, 210145_AT, 206157_AT, 203888_AT, 212977_AT,224341_X_AT, 203887_S_AT, 225097_AT, 205495_S_AT, 1555756_A_AT,1555759_A_AT, 202638_S_AT, 213293_S_AT GO: 0007165~signal 212298_AT,209555_S_AT, 227948_AT, 223660_AT, 210360_S_AT, 219412_AT, transduction222858_S_AT, 205798_AT, 206488_S_AT, 205960_AT, 206171_AT, 225173_AT,220066_AT, 200878_AT, 237442_AT, 242903_AT, 225166_AT, 218589_AT,203655_AT, 205891_AT, 207610_S_AT, 225171_AT, 209568_S_AT, 220307_AT,239519_AT, 230266_AT, 209684_AT, 218856_AT, 1553982_A_AT, 223502_S_AT,203104_AT, 212977_AT, 223939_AT, 224341_X_AT, 204834_AT, 206637_AT,228766_AT, 1555756_A_AT, 230925_AT, 214581_X_AT, 214297_AT, 218501_AT,202727_S_AT, 1405_I_AT, 228708_AT, 221060_S_AT, 202609_AT, 226218_AT,223501_AT, 205898_AT, 205099_S_AT, 211661_X_AT, 214841_AT, 204116_AT,232746_AT, 225207_AT, 207433_AT, 227265_AT, 225188_AT, 221463_AT,205419_AT, 232068_S_AT, 209906_AT, 228368_AT, 1554992_AT, 201952_AT,210510_S_AT, 204655_AT, 225189_S_AT, 230559_X_AT, 214054_AT,203037_S_AT, 210264_AT, 211676_S_AT, 1552798_A_AT, 216250_S_AT,237904_AT, 208712_AT, 225097_AT, 219994_AT, 1555759_A_AT, 241929_AT,219434_AT, 201951_AT GO: 0009617~response 237252_AT, 1405_I_AT,204655_AT, 1552553_A_AT, 221060_S_AT, 1552798_A_AT, to bacterium210145_AT, 203888_AT, 211661_X_AT, 222062_AT, 224341_X_AT, 203887_S_AT,207433_AT, 205495_S_AT, 1555759_A_AT, 220066_AT, 232068_S_AT, 37145_ATGO: 0048519~negative 213891_S_AT, 1553995_A_AT, 212298_AT, 224218_S_AT,205798_AT, 201278_AT, regulation of biological 228057_AT, 202284_S_AT,220066_AT, 203939_AT, 228490_AT, 203665_AT, process 205891_AT,201279_S_AT, 204998_S_AT, 208816_X_AT, 201565_S_AT, 239519_AT,203753_AT, 201590_X_AT, 204999_S_AT, 226066_AT, 223502_S_AT,215990_S_AT, 221815_AT, 225337_AT, 212143_S_AT, 224341_X_AT, 201422_AT,222146_S_AT, 222651_S_AT, 229435_AT, 201005_AT, 215813_S_AT,210095_S_AT, 205681_AT, 205128_X_AT, 214211_AT, 1560485_AT, 212171_X_AT,213503_X_AT, 63825_AT, 1405_I_AT, 221060_S_AT, 210427_X_AT, 201566_X_AT,228964_AT, 226218_AT, 223501_AT, 212387_AT, 223398_AT, 244579_AT,218559_S_AT, 205566_AT, 207233_S_AT, 222062_AT, 218502_S_AT, 206835_AT,207433_AT, 210512_S_AT, 202827_S_AT, 222670_S_AT, 208436_S_AT,232068_S_AT, 87100_AT, 211527_X_AT, 212382_AT, 203140_AT, 203980_AT,217757_AT, 204655_AT, 210510_S_AT, 210513_S_AT, 1552798_A_AT,206675_S_AT, 213931_AT, 238669_AT, 212614_AT, 208712_AT, 210258_AT,210757_X_AT, 212386_AT, 206134_AT, 225097_AT, 1555759_A_AT, 1556423_AT,201280_S_AT, 223394_AT GO: 0050864~regulation 203140_AT, 222062_AT,204116_AT, 207433_AT, 202284_S_AT, 223501_AT, of B cell activation223502_S_AT, 215990_S_AT GO: 0001525~angiogenesis 203665_AT, 214297_AT,213503_X_AT, 212171_X_AT, 212298_AT, 204575_S_AT, 208816_X_AT,210510_S_AT, 210427_X_AT, 210513_S_AT, 239519_AT, 201590_X_AT,222877_AT, 202827_S_AT, 210512_S_AT, 211527_X_AT, 200878_AT GO:0048869~cellular 220333_AT, 210495_X_AT, 229221_AT, 212298_AT,222877_AT, 205798_AT, developments process 201278_AT, 211962_S_AT,242871_AT, 203936_S_AT, 209348_S_AT, 230360_AT, 204141_AT, 200878_AT,1569149_AT, 201279_S_AT, 204998_S_AT, 239519_AT, 201565_S_AT,221266_S_AT, 233540_S_AT, 204999_S_AT, 226066_AT, 212190_AT,215990_S_AT, 212143_S_AT, 220484_AT, 201005_AT, 243556_AT, 210095_S_AT,201324_AT, 212464_S_AT, 216442_X_AT, 212171_X_AT, 214297_AT,204575_S_AT, 227240_AT, 201566_X_AT, 211719_X_AT, 228964_AT, 226218_AT,207233_S_AT, 207433_AT, 210512_S_AT, 202827_S_AT, 205419_AT,211527_X_AT, 204465_S_AT, 1554992_AT, 203140_AT, 1560960_AT, 201952_AT,1569150_X_AT, 203980_AT, 220935_S_AT, 210510_S_AT, 210513_S_AT,213931_AT, 204105_S_AT, 208712_AT, 210757_X_AT, 229797_AT, 201280_S_AT,201951_AT GO: 0002694~regulation 203140_AT, 205891_AT, 203665_AT,226218_AT, 223501_AT, 215990_S_AT, of leukocyte activation 223502_S_AT,205798_AT, 210895_S_AT, 222062_AT, 204116_AT, 207433_AT, 202284_S_AT GO:0044243~multicellular 201069_AT, 204575_S_AT, 203936_S_AT, 204475_ATorganismal catabolic process GO: 0030574~collagen 201069_AT,204575_S_AT, 203936_S_AT, 204475_AT cataboltc process GO: 0016477~cell216442_X_AT, 210495_X_AT, 229221_AT, 1560960_AT, 212298_AT, 210510_S_AT,migration 1405_I_AT, 204655_AT, 239519_AT, 211719_X_AT, 222877_AT,204268_AT, 204105_S_AT, 212614_AT, 207433_AT, 202827_S_AT, 1555759_A_AT,235286_AT, 202638_S_AT, 212464_S_AT GO: 0045595~regulation 212298_AT,209555_S_AT, 1405_I_AT, 201566_X_AT, 221040_S_AT, 226218_AT of celldifferentiation 218559_S_AT, 205798_AT, 207233_S_AT, 206488_S_AT,210895_S_AT, 204116_AT, 209348_S_AT, 222670_S_AT, 232068_S_AT,1569149_AT, 203140_AT, 1569150_X_AT, 204998_S_AT, 220935_S_AT,210510_S_AT, 204655_AT, 239519_AT, 201565_S_AT, 1552798_A_AT,233540_S_AT, 204999_S_AT, 226066_AT, 215990_S_AT, 213931_AT,212143_S_AT, 204105_S_AT, 208712_AT, 224341_X_AT, 228766_AT,1555759_A_AT, 241929_AT, 210095_S_AT GO: 0032879~regulation 212298_AT,212171_X_AT, 209555_S_AT, 63825_AT, 228708_AT, 205566_AT, oflocalization 206488_S_AT, 207433_AT, 203936_S_AT, 210512_S_AT, 87100_AT,220066_AT, 211527_X_AT, 228490_AT, 203665_AT, 203140_AT, 205891_AT,210510_S_AT, 239519_AT, 210513_S_AT, 212190_AT, 210145_AT, 221815_AT,215990_S_AT, 206157_AT, 212143_S_AT, 225337_AT, 238669_AT, 228766_AT,1555756_A_AT, 209392_AT, 1556423_AT, 241929_AT, 210095_S_AT,215813_S_AT, 202638_S_AT, 205128_X_AT GO: 0050729~positive 205891_AT,224341_X_AT, 203980_AT, 204655_AT, 1405_I_AT, 221060_S_AT, regulation of1555759_A_AT, 232068_S_AT, 1552798_A_AT, 210145_AT inflammatory responseGO: 0007186~G-protein 218589_AT, 209906_AT, 205891_AT, 207610_S_AT,223660_AT, 1405_I_AT, coupled receptor protein 204655_AT, 210264_AT,205898_AT, 205099_S_AT, 237904_AT, 211661_X_AT, signaling pathway212977_AT, 210258_AT, 232746_AT, 223939_AT, 206171_AT, 206637_AT,1555759_A_AT, 209392_AT, 205419_AT GO: 0051270~regulation 228490_AT,203665_AT, 203140_AT, 212298_AT, 212171_X_AT, 63825_AT, of cell motion210510_S_AT, 239519_AT, 210513_S_AT, 212190_AT, 215990_S_AT, 221815_AT,212143_S_AT, 205566_AT, 225337_AT, 203936_S_AT, 210512_S_AT, 209392_AT,1556423_AT, 87100_AT, 211527_X_AT, 210095_S_AT, 202638_S_AT GO:0048518~positive 213891_S_AT, 229221_AT, 212298_AT, 209555_S_AT,227948_AT, 222838_AT, regulation of biological 242794_AT, 205798_AT,206488_S_AT, 217999_S_AT, 217997_AT, 209348_S_AT, process 203936_S_AT,202284_S_AT, 220066_AT, 232333_AT, 200878_AT, 1569149_AT, 205891_AT,203665_AT, 201565_S_AT, 239519_AT, 203753_AT, 234645_AT, 210145_AT,226066_AT, 215990_S_AT, 206157_AT, 223502_S_AT, 212143_S_AT, 215602_AT,224341_X_AT, 222146_S_AT, 228766_AT, 1555756_A_AT, 243556_AT, 229435_AT,215813_S_AT, 210095_S_AT, 205128_X_AT, 212171_X_AT, 218501_AT,1553906_S_AT, 227240_AT, 1405_I_AT, 201566_X_AT, 235457_AT, 221060_S_AT,228964_AT, 226218_AT, 223501_AT, 212387_AT, 218559_S_AT, 207233_S_AT,210895_S_AT, 222062_AT, 204116_AT, 207433_AT, 222670_S_AT, 210512_S_AT,232068_S_AT, 208436_S_AT, 211527_X_AT, 244414_AT, 212382_AT, 209906_AT,1554992_AT, 203140_AT, 1569150_X_AT, 242405_AT, 203980_AT, 210510_S_AT,204655_AT, 1552553_A_AT, 230559_X_AT, 210513_S_AT, 1565754_X_AT,1552798_A_AT, 208978_AT, 225842_AT, 213931_AT, 238669_AT, 1565752_AT,204105_S_AT, 208712_AT, 212386_AT, 225097_AT, 1555759_A_AT, 241929_AT,202638_S_AT, 223394_AT GO: 001816~cytokine 224341_X_AT, 203980_AT,1552553_A_AT, 209348_S_AT, 221060_S_AT, production 220066_AT,232068_S_AT, 1552798_A_AT, 211661_X_AT GO: 0007610~behavior 209906_AT,1554992_AT, 1405_I_AT, 204655_AT, 202609_AT, 222877_AT, 205898_AT,205099_S_AT, 211661_X_AT, 220484_AT, 225097_AT, 207433_AT, 229797_AT,223092_AT, 1555759_A_AT, 209392_AT, 221463_AT, 235286_AT GO:00550878~regulation 237252_AT, 213503_X_AT, 209555_S_AT, 208816_X_AT,210427_X_AT, of body fluid levels 201590_X_AT, 203888_AT, 206488_S_AT,206835_AT, 203887_S_AT, 228766_AT, 235944_AT, 241929_AT, 201005_AT,203060_S_AT GO: 0032496~response 237252_AT, 1405_I_AT, 204655_AT,221060_S_AT, 1552798_A_AT, 210145_AT, to lipopolysaccharide 203888_AT,211661_X_AT, 224341_X_AT, 203887_S_AT, 207433_AT, 1555759_A_AT,232068_S_AT, 220066_AT GO: 0002683~negative 205798_AT, 203665_AT,203140_AT, 222062_AT, 217757_AT, 207433_AT, regulation of immune220066_AT, 226218_AT, 215990_S_AT GO: 0051674~localization 216442_X_AT,210495_X_AT, 229221_AT, 1560960_AT, 212298_AT, 210510_S_AT, of cell1405_I_AT, 204655_AT, 239519_AT, 211719_X_AT, 222877_AT, 204268_AT,204105_S_AT, 212614_AT, 207433_AT, 202827_S_AT, 1555759_A_AT, 235286_AT,202638_S_AT, 212464_S_AT GO: 0048870~cell motility 216442_X_AT,210495_X_AT, 229221_AT, 1560960_AT, 212298_AT, 210510_S_AT, 1405_I_AT,204655_AT, 239519_AT, 211719_X_AT, 222877_AT, 204268_AT, 204105_S_AT,212614_AT, 207433_AT, 202827_S_AT, 1555759_A_AT, 235286_AT, 202638_S_AT,212464_S_AT GO: 0046903~secretion 203665_AT, 205891_AT, 207542_S_AT,213503_X_AT, 201279_S_AT, 208816_X_AT, 1405_I_AT, 204655_AT,210427_X_AT, 1552553_A_AT, 201590_X_AT, 227134_AT, 223501_AT,223502_S_AT, 201278_AT, 206835_AT, 210757_X_AT, 1555759_A_AT, 209047_AT,201280_S_AT, 235286_AT GO: 0006928~cell motion 210495_X_AT, 216442_X_AT,229221_AT, 212298_AT, 1405_I_AT, 211719_X_AT, 210360_S_AT, 222877_AT,204268_AT, 207433_AT, 202827_S_AT, 235286_AT, 1560960_AT, 201952_AT,204655_AT, 210510_S_AT, 239519_AT, 203037_S_AT, 212614_AT, 204105_S_AT,1555759_A_AT, 209392_AT, 201005_AT, 201951_AT, 202638_S_AT, 212464_S_ATGO: 0048514~blood 203665_AT, 214297_AT, 213503_X_AT, 212171_X_AT,212298_AT, 204575_S_AT, vessel morphogenesis 208816_X_AT, 210510_S_AT,239519_AT, 210427_X_AT, 210513_S_AT, 201590_X_AT, 222877_AT,211962_S_AT, 202827_S_AT, 210512_S_AT, 211527_X_AT, 200878_AT GO:0001501~skeletal 201069_AT, 213503_X_AT, 1569150_X_AT, 210427_X_AT,201590_X_AT, system development 224218_S_AT, 204653_AT, 244579_AT,212143_S_AT, 212614_AT, 206835_AT, 218502_S_AT, 203936_S_AT,202827_S_AT, 223092_AT, 222651_S_AT, 203060_S_AT, 210095_S_AT,1569149_AT GO: 0050867~positive 203140_AT, 205891_AT, 221060_S_AT,1552798_A_AT, 226218_AT, 223501_AT, regulation of cell 223502_S_AT,215990_S_AT, 205798_AT, 210895_S_AT, 224341_X_AT, 204116_AT, activation202284_S_AT, 232068_S_AT GO: 0030247~polysaccharide 229221_AT,216442_X_AT, 210495_X_AT, 212171_X_AT, 210513_S_AT, binding 211719_X_AT,212190_AT, 206157_AT, 1555756_A_AT, 210512_S_AT, 220066_AT, 209392_AT,211527_X_AT, 212464_S_AT GO: 0001871~pattern 229221_AT, 216442_X_AT,210495_X_AT, 212171_X_AT, 210513_S_AT, binding 211719_X_AT, 212190_AT,206157_AT, 1555756_A_AT, 210512_S_AT, 220066_AT, 209392_AT, 211527_X_AT,212464_S_AT GO: 0004222~metalloendopeptidase 201069_AT, 206134_AT,204575_S_AT, 229004_AT, 203936_S_AT, 202827_S_AT, activity 204475_AT GO:0002698~negative 205798_AT, 203665_AT, 203140_AT, 217757_AT, 226218_AT,215990_S_AT regulation of immune effector process GO: 0002698~positive205891_AT, 212171_X_AT, 203980_AT, 1405_I_AT, 204655_AT, 221060_S_AT,regulation of response to 210513_S_AT, 1552798_A_AT, 210145_AT,224341_X_AT, 1555759_A_AT, external stimulus 210512_S_AT, 232068_S_AT,211527_X_AT GO: 0010033~response 237252_AT, 229221_AT, 202435_S_AT,1405_I_AT, 201566_X_AT, 221060_S_AT, to organic substance 202609_AT,218934_S_AT, 204058_AT, 211661_X_AT, 202434_S_AT, 207433_AT,202827_S_AT, 202284_S_AT, 209047_AT, 220066_AT, 232068_S_AT, 203665_AT,207542_S_AT, 202436_S_AT, 217757_AT, 204059_S_AT, 203980_AT, 204655_AT,202437_S_AT, 201565_S_AT, 1552798_A_AT, 210145_AT, 213931_AT, 203888_AT,238669_AT, 208712_AT, 203887_S_AT, 224341_X_AT, 1555756_A_AT,1555759_A_AT, 215813_S_AT, 209122_AT, 205128_X_AT Term Genes Enrichedamong top downregulated genes: GO: 0007275~multicellular BMP8B, TEAD4,FLOT2, IRX3, ADAMTS1, DZIP1, CSPGS, organismal COL8A2, EBF3, TSPAN2,FKBP4, HK2P1, CXCR4, GFI1, development FLOT2, SIK1, DMRT2, TPDS2, TPDS2,WT1, TPDS2, WNT3, LGR4, SLC1A3, BCL11A, BCL2, SPRY1, PCDH8, CNTN4,BCL11A, ECE2, BMP8B, CXCR4, CAV1, WT1, KCNQ4, POU4F2, CXCR4, KAZ, OSR2,RET, COL8A2, BCL11A, BCL2, PKP2 GO: 0048731~system BMP8B, TEAD4, FLOT2,IRX3, ADAMTS1, CSPG5, development COLBA2, TSPAN2, HK2P1, CXCR4, GFI1,FLOT2, DMRT2, TPD52, TPD52, WT1, TPD52, WNT3, LGR4, SLC1A3, BCL2,BCL11A, SPRY1, PCDH8, CHTN4, BCL11A, ECE2, BMP8B, CXCR4, WT1, CAV1,KCNQ4, POU4F2, CXCR4, KAZ, OSR2, RET, COL8A2, BCL11A, BCL2, PKP2 GO:0048513~organ BMP8B, TEAD4, FLOT2, ADAMTS1, COLBA2, HK2P1, developmentCXCR4, GFI1, FLOT2, DMRT2, TPD52, TPD52, WT1, TPD52, WNT3, LGR4, BCL2,BCL11A, SPRY1, PCDH8, CMTN4, BCL11A, ECE2, BMP8B, CXCR4, WT1, CAV1,KCNQ4, POU4F2, CXCR4, KAZ, RET, OSR2, COL8A2, BCL2, BCL11A, PKP2 GO:0048856~anatomical BMP8B, TEAD4, FLOT2, IRX3, ADAMTS1, CSPG5, structuredevelopment COL8A2, TSPAN2, HK2P1, CXCR4, GFI1, FLOT2, DMRT2, TPD52,TPD52, WT1, TPD52, WNT3, LGR4, SLC1A3, BCL2, BCL11A, SPRY1, PCDH8,CNTN4, BCL11A, ECE2, BMP8B, CXCR4, WT1, CAV1, KCNQ4, POU4F2, CXCR4, KAZ,OSR2, RET, COL8A2, BCL11A, BCL2, PKP2 GO: 0030154~cell BMP8B, TDRD7,TEAD4, IRX3, DZIP1, CSPG5, TSPAN2, differentiation CXCR4, GFI1, SIK1,TPO52, TPD52, WT1, TPD52, WNT3, SLC1A3, BCL11A, BCL2, SPRY1, CNTN4,BCL11A, ECE2, BMP8B, CAV1, WT2, CXCR4, POU4F2, CXCR4, KAZ, RET, BCX11A,BCL2 GO: 0032502~developmental BMP8B, TDRD7, TEAD4, FLOT2, IRX3,ADAMTS1, DZIP1, process CSPG5, COLBA2, EBF3, TSPAN2, FKBP4, HK2P1,CXCR4, GFI1, FLOT2, SIK1, DMRT2, TPD52, TPD52, WT1, TPD52, WNT3, LGR4,SLC1A3, BCL11A, BCL2, SPRY1, PCDH8, CNTN4, BCL11A, ECE2, BMP8B, CXCR4,CAV1, WT1, KCNQ4, POU4F2, CXCR4, KAZ, OSR2, RET, COLBA2, BCL11A, BCL2,PKP2 GO: 0003006~reproductive TDRD7, LGR4, BCL2, AQAMTS1, DZIP1, WT1,CXCR4, developmental FKBP4, CXCR4, CXCR4, BCL2, DMRT2, WT1 process GO:0048869~cellular BMP8B, TDRD7, TEAD4, IRX3, DZIP1, CSPG5, TSPAN2,developmental process CXCR4, GFI1, SIK1, TPD52, TPD52, WT1, TPD52, WNT3,SLC1A3, BCL11A, BCL2, SPRY1, CNTN4, BCL11A, ECE2, BMP8B, CAV1, WT1,CXCR4, POU4F2, CXCR4, KAZ, RET, BCL11A, BCL2 GO: 0009653~anatomicalTEAD4, ADAMTS1, CQLBA2, CXCR4, GFI1, TPD52, TPD52, structuremorphogenesis WT1, TPD52, WNT3, LGR4, SLC1A3, BCL2, CNTN4, PCDH8, WT1,CXCR4, CAV1, KCNQ4, POU4F2, OSR2, RET, CXCR4, COL8A2, BCL2 Enrichedamong top upregulated genes: GO: 0005886~plasma ADAP2, NT5E, FN1, CD44,MFI2, NRP1, CD36, ADORA3, membrane PCDHGA12, RAB3S, IL7R. KCNQ3, GLDN,CD109, IFNGR1, EMR2, CD244, SLC43A2, ANXA2P1, CYBB, LILRB1, SLC38A6,CSF1R, CXCR7, GPC1, CD36, APBB1IP, NGEF, CD9, ATP1B1, GBP2, PLIN2,PTGS1, FTHL3, THBD, CSPG4, IFNGR1, TLR4, FN1, SLC12A6, TNFSF13B, CX3CR1,CD52, CCR1, PSD3, LILRB2, PCDHGA12, SLC7A11, TLR4, AQP1, GBP5, RASGRF1,C3AR1, TRPM8, NRP1, SLC6A6, IFNGR1, PTPRO, PTGS1, NRCAM, APBB1IP, ITGB5,PSD3, ICAM1, ATP1B1, IL10RA, MMP2, CD180, SLC43A2, NRP2, SYTL1, ST3GAL5,CD109, EVL, CD36, ADORA3, PTRF, ATP6V0D2, NOD2, PCDH7, APBB1IP, NT5E,STEAP1, LPAR6, SLC41A2, COL6A1, LOC100131909, HMOX1, AQP1, GBP2,ANXA2P2, NRP1, ABCC3, TM7SF4, SLC7A11, TNFSF13B, PTRF, LMNA, MCOLN3,THBD, TLR4, SUCNR1, P2RY14, CLEC7A, ENPP2, ABCB1, PTGS1, EMP1, FN1, FN1,ANXA2P1, NGEF, ANXA2P1, EPS8, DIXDC1, IL7R, CD52, PTAFR, CD86, IL27RA,IL2RG, CXCR7, ANKH, RAPH1, MMP14, GPR183, SLC41A2, MDGA1, ALCAM, RAPH1,TLR4, GPR35, ITG87, ADORA3, THBD, SLC41A2, MTUS1, RGS13, OLR1, ADAP2,MCOLN3, PLEKHO1, CD36, TREM1, ALCAM GO: 0031226~intrinsic to MFI2, CD44,CD36, ADORA3, ST3GAL5, CD36, ADORA3, plasma membrane KCNQ3, PCDH7,IFNGR1, STEAP1, LOC100131909, AQP1, ABCC3, CYBB, CSF1R, GPC1, TLR4,THBD, CD36, ENPP2, CD9, ATP1B1, THBD, CSPG4, IFNGR1, TLR4, EPS8,SLC12A6, CD52, CD52, CX3CR1, CCR1, PTAFR, IL27RA, IL2RG, LILRB2, MMP14,ANKH, AQP1, GPR183, TLR4, C3AR1, MDGA1, SLC6A6, GPR35, IFNGR1, PTPRO,TLR4, ITG87, ADORA3, THBD, NRCAM, OLR1, CD36, ITG85, ICAM1, ATP1B1 GO:0016020~membrane NT5E, MFI2, NRP1, ADORA3, SLAMF7, RAB38, IL7R, PDK4,KCNQ3, GDPD1, PHLDA1, CD109, MPZL3, GCNT1, CD244, SLC43A2, FADS3,ANXA2P1, CYBB, RHBDF1, ABHD2, CSF1R, GPC1, CD36, PTGS1, FTHL3, TNFRSF21,ABHD2, FN1, TNFSF13B, CX3CR1, CCR1, MARCH1, LILRB2, PCDHGA12, HMCN1,AQP1, GCNT1, RASGRF1, POPDC3, HAVCR2, IFNGR1, PHLDA1, PTGS1, FADS3,NRCAM, C4ORF34, ADAMDEC1, ICAM1, GCNT1, ATP1B1, IL10RA, SLC37A2,SLC43A2, SYTL1, NRP2, ATP9A, CYP1B1, DAPP1, GUPR1, CD109, TMEM39A, CD36,PTRF, ATP6V0D2, NOD2, PCDH7, STEAP1, TMEM158, HMOX1, LOC100131909, GBP2,ANXA2P2, NRP1, ABCC3, TNFRSF21, PLA2G4A, TNFSF13B, LPCAT2, TBXAS1, PTRF,DOCK4, LMNA, SUCNR1, THBD, P2RY14, KMO, CLEC7A, PTGS1, NGEF, ANXA2P1,IL7R, CD52, PARM1, CD86, IL27RA, CXCR7, VEGFA, RAPH1, VEGFA, C4ORF34,MDGA1, ALCAM, RAPH1, GPR35, ITG87, RGS13, DAB2, ADAP2, OLR1, MCOLN3,DAB2, ALCAM, PAQR5, ADAP2, FN1, CD44, CD36, CYP1B1, PCDHGA12, PHLDA1,AGPAT9, PAQR5, ATP10A, GLDN, IFNGR1, ABHD2, EMR2, LILRB1, SLC38A6,C40RF34, CXCR7, APBB1IP, NGEF, C09, ATP1B1, GBP2, PLIN2, THBD, VEGFA,CSPG4, ACPP, IFNGR1, TLR4, SLC12A6, CD52, ABHD2, PSD3, SLC7A11, TLR4,GBP5, CALHM2, C3AR1, TRPM8, NRP1, VEGFA, SLC6A6, PTPRO, GBP3, UGCG,HIPK2, APBB1IP, KMO, PSD3, ITGB5, GLIPR1, MMP2, CD180, ST3GAL5, DAB2,EVL, ADORA3, DSE, APBB1IP, NT5E, LPAR6, SLC41A2, COL6A1, CYP1B1, AQP1,CALHM2, DAB2, SLAMF8, TM7SF4, SLC7A11, ABHD2, MCOLN3, TLR4, LFNG, ENPP2,EMP1, ABCB1, FN1, GDPD1, FN1, ANXA2P1, RAB278, EPS8, DIXDC1, PTAFR,CNIH3, IL2RG, PDK4, SLAMF8, MMP14, ANKH, ABHD2, GPR183, CKLF, SLC41A2,HAVCR2, CYP1B1, TLR4, THBD, ADORA3, SLC41A2, MTUS1, PLEKHO1, CD36, TREM1GO: 0005887~integral to MFI2, CD44, CD36, ADORA3, ST36AL5, CD36, ADORA3,plasma membrane KCNQ3, PCDH7, IFNGR1, STEAP1, LOC10Q131909, AQP1, ABCC3,CYBB, CSF1R, GFC1, TLR4, THBD, CD36, ENPP2, CD9, ATP181, THBD, CSPG4,IFNGR1, TLR4, EPS8, SLC12A6, CD52, CD52, CX3CR1, CCR1, PTAFR, IL27RA,IL2RG, LILRB2, MMP14, ANKH, AQP1, GPH183, TLR4, C3AR1, SLC6A6, GPR35,IFNGR1, PTPRO, TLR4, ITG87, ADORA3, THBD, NRCAM, OLR1, CD36, ITG85,ICAM1, ATP181 GO: 0044459~plasma FN1, MFI2, CD44, CD36, ADORA3, SVTL1,ST3GAL5, membrane part RAB38, IL7R, CD36, EVL, ADORA3, KCNQ3, PTRF,ATP6VOD2, PCDH7, AP881IP, IFNGR1, STEAP1, HMOX1, LOC100131909, AQP1,G8P2, CD244, ABCC3, CYBB, SLC38A6, PTRF, CSF1R, GPC1, TLR4, THBD, CD36,CLEC7A, APBB1IP, EWPP2, CD9, ATP1B1, ABCB1, GBF2, FN1, THBO, FN1, CSPG4,IFNGR1, TLR4, FN1, EPS8, DIXDC1, SLC12A6, IL7R, CD52, CD52, CX3CR1,CCR1, PTAFR, CD86, PSD3, IL27RA, IL2RG, LILRB2, MMP14, ANKH, RAPH1,AQP1, GPR183, TLR4, GBP5, C3AR1, MDGA1, TRPM8, ALCAM, RAPH1, SLC6A6,GPR35, IFNGR1, PTPRO, TLR4, ITGB7, ADORA3, THBD, NRCAM, OLR1, APBB1IP,CD36, PSD3, ITG85, ALCAM, ICAM1, ATP1B1 GO: 0005576~extracellularGLIPR1, CD44, MFI2, FN1, MMP2, NRP1, IL7R, GLIPR1, region CD109, MMP9,CD109, GNLY, HMOX1, COL6A1, ANXA2P2, NRP1, ANXA2P1, SERPINE2, TNFSF13B,PTX3, IGFBP3, PRSS23, THBD, GPC1, IFI30, FGL2, GNLY, COL22A1, ENPP2,LFNG, IGFBP3, PGA5, PLIN2, FN1, THBD, FN1, ACPP, VEGFA, ANXA2P1, MMP19,CCL5, ANXA2P1, FN1, IL7R, TNFSF13B, STATH, IL10, FGL2, HMCN1, VEGFA,MMP14, CCL24, VEGFA, MMP1, CKLF, A2M, ADAMTS15, CCL5, NRP1, VEGFA, TH8D,OLR1, ADAMDEC1, CTSL1, CCL5, VASH1, TREM1, ICAM1 GO: 0031224~intrinsicto PAQR5, NT5E, CD44, MFI2, NRP1, CD36, ADORA3, membrane SLAMF7,PCDHGA12, IL7R, AGPAT9, ATP10A, PAQR5, GDPD1, KCNQ3, GLDN, CD109,IFNGR1, MPZL3, ABHD2, EMR2, GCNT1, CD244, SLC43A2, FADS3, CTBB, RHBDF1,LILRB1, ABHD2, SLC38A6, C4ORF34, CSF1R, CXCR7, GPC1, CD36, CD9, ATP1B1,TNFRSF21, THBD, ACPP, CSPG4, ABHD2, IFNGR1, TLR4, SLC12A6, TNFSF13B,CX3CR1, CD52, CCR1, ABHD2, MARCH1, LILRB2, PCDHGA12, SLC7A11, TLR4,GCNT1, AQP1, CALHM2, C3AR1, TRPM8, NRP1, SLC6A6, HAVCR2, POPDC3, IFNGR1,PTPRO, FADS3, GBP3, C4ORF34, NRCAM, UGCG, ADAMDEC1, KMO, ITG85, ICAM1,GCNT1, ATP1B1, GLIPR1, IL10RA, SLC37A2, CD180, SLC43A2, NRP2, ST3GAL5,ATP9A, CD109, GLIPR1, CD36, TMEM39A, ADORA3, DSE, PCDH7, NT5E, STEAP1,TMEM15B, LPAR6, SLC41A2, LOC100131909, AQP1, CALHM2, NRP1, SLAMF8,ABCC3, TM7SF4, SLC7A11, TNFRSF21, PLA2G4A, LPCAT2, TNFSF13B, ABHD2,TBXAS1, MCOLN3, THBD, TLR4, SUCNR1, P2RY14, KMO, CLEC7A, ENPP2, LFNG,ABCB1, EMP1, GDPD1, RAB27B, EPS8, JL7R, CD52, PARM1, PTAFR, CNIH3, CD86,IL27RA, CXCR7, IL2RG, SLAMF8, ANKH, MMP14, GPR183, ABHD2, CKLF, C4ORF34,SLC41A2, MDGA1, HAVCR2, ALCAM, TLR4, GPR35, ITGB7, ADORA3, THBD,SLC41A2, OLR1, MCOLN3, CD36, TREM1, ALCAM GO: 0004871~signal PAQR5,IL10RA, CD44, NRP1, CD36, ADORA3, CD180, transducer activity SLAMF7,NRP2, IL7R, CD36, PDK4, ADORA3, PAQR5, EPAS1, IFNGR1, LPAR6, SLA, HMOX1,LOC100131909, EMR2, CD244, NRP1, TNFRSF21, RHBDF1, LILRB1, CSF1R, CXCR7,SUCNR1, TLR4, THBD, P2RY14, CD36, CLEC7A, ENPP2, TNFRSF21, THBD, CSPG4,IFNGR1, CCL5, TLR4, EPS8, DIXDC1, IL7R, CX3CR1, CCR1, PTAFR, CD86,IL27RA, IL2RG, CXCR7, PDK4, LILRB2, HMCN1, GPR183, TLR4, C3AR1, TRPM8,NRP1, CCL5, DOK2, IFNGR1, PTPRO, TLR4, GPR35, SKIL, ITG87, THBD, ADORA3,SLA, RGS13, OLR1, CCL5, CD36, ITGB5, TREM1, ICAM1 GO: 0060089~molecularPAQR5, IL10RA, CD44, NRP1, CD36, ADORA3, CD180, transducer activitySLAMF7, NRP2, IL7R, CD36, PDK4, ADORA3, PAQR5, EPAS1, IFNGR1, LPAR6,SLA, HMOX1, LOC100131909, EMR2, CD244, NRP1, TNFRSF21, RHBDF1, LILRB1,CSF1R, CXCR7, SUCNR1, TLR4, TH8D, P2RY14, CD36, CLEC7A, ENPP2, TNFRSF21,THBD, CSPG4, IFNGR1, CCL5, TLR4, EPS8, DIXDC1, IL7R, CX3CR1, CCR1,PTAFR, CD86, IL27RA, IL2RG, CXCR7, PDK4, ULRB2, HMCN1, GPR183, TLR4,C3AR1, TRPM8, NRP1, CCL5, DOK2, IFNGR1, PTPRO, TLR4, GPR35, SKIL, ITGB7,THBD, ADORA3, SLA, RGS13, OLR1, CCL5, CD36, ITGB5, TREM1, ICAM1 GO:0004872~receptor PAQR5, CD44, IL10RA, NRP1, CD36, ADORA3, CD180,activity SLAMF7, NRP2, IL7R, CD36, ADORA3, PAQR5, IFNGR1, LPAR6,LOC100131909, EMR2, CD244, NRP1, TNFRSF21, RHBDF1, LILRB1, CSF1R, CXCR7,SUCNR1, TLR4, TH8D, CD36, P2RY14, CLEC7A, ENPP2, TNFRSF21, THBD, IFNGR1,TLR4, EPS8, IL7R, CX3CR1, CCR1, PTAFR, CD86, IL27HA, IL2RG, CXCR7,LILRB2, HMCN1, GPR183, TLR4, C3AR1, TRPM8, NRP1, GPR35, PTPRO, IFNGR1,TLR4, ITGB7, ADORA3, THBD, OLR1, CD36, ITGB5, TREM1, ICAM1 GO:0044425~membrane NT5E, PAQR5, FN1, CD44, MFI2, NRP1, CD36, CYP1B1, partADORA3, SLAMF7, PCDHGA12, RAB38, IL7R, AGPAT9, ATP10A, PAQR5, GDPD1,KCNQ3, GLDN, CD109, MPZL3, IFNGR1, ABHD2, EMR2, GCNT1, CD244, SLC43A2,FADS3, CYBB, RHBDF1, LILRB1, ABHD2, SLC38A6, C4ORF34, CSF1R, CXCR7,GPC1, CD36, APBB1IP, CD9, ATP1B1, GBP2, PUN2, PTGS1, TNFRSF21, THBD,ACPP, CSPG4, ABHD2, IFNGR1, TLR4, FN1, SLC12A6, TNFSF13B, CX3CR1, CD52,CCR1, ABMD2, MARCH1, PSD3, LILRB2, PCDHGA12, SLC7A11, TLR4, GCNT1, AQP1,GBP5, CALHM2, C3AR1, TRPM8, NRP1, SLC6A6, HAVCR2, POPDC3, PTPRO, IFNGR1,PTGS1, FADS3, GBP3, C4ORF34, NRCAM, UGCG, ADAMDEC1, KMO, APBB1IP, ITGB5,PSD3, ICAM1, GCNT1, ATP1B1, GLIPR1, IL10RA, SLC37A2, CD180, SLC43A2,NRP2, SYTL1, ST3GAL5, ATP9A, CYP1B1, DAPP1, DAB2, CD109, GLIPR1, EVL,CD36, TMEM39A, ADORA3, DSE, ATP6V0D2, PTRF, PCDH7, NT5E, APBB1IP,STEAP1, TMEM158, SLC41A2, LPAR6, LOC100131909, HMOX1, CYP1B1, CALHM2,AQP1, DAB2, GBP2, NRP1, SLAMF8, ABCC3, TM7SF4, SLC7A11, TNFRSF21,PLA2G4A, LPCAT2, TNFSF13B, ABHD2, TBXAS1, PTRF, DOCK4, MCOLN3, THBD,TLR4, SUCNR1, P2RY14, KMO, CLEC7A, ENPP2, LFNG, ABCB1, EMP1, PTGS1, FN1,GDPD1, FN1, RAB27B, EPS8, DIXDC1, IL7R, CD52, PARM1, PTAFR, CNIH3, CD86,IL27RA, CXCR7, IL2RG, SLAMF8, ANKH, RAPH1, MMP14, GPR183, ABHD2, CKLF,C4ORF34, SLC41A2, MDGA1, ALCAM, HAVCR2, CYP1B1, RAPH1, TLR4, GPR35,ITGB7, ADORA3, THBD, SLC41A2, DAB2, OLR1, MCOLN3, DAB2, CD36, TREM1,ALCAM GO: 0016021~integral to PAQR5, CD44, MFI2, NRP1, CD36, ADORA3,SLAMF7, membrane PCDHGA12, IL7R, AGPAT9, ATP10A, PAQR5, GDPD1, KCNQ3,GLDN, IFNGR1, MPZL3, ABHD2, EMR2, GCNT1, CD244, SLC43A2, FADS3, CYBB,RHBDF1, LILRB1, ABHD2, SLC38A6, C4ORF34, CSF1R, CXCR7, GPC1, CD36, CD9,ATP1B1, TNFRSF21, THBD, ACPP, CSPG4, ABHD2, IFNGR1, TLR4, SLC12A6,TNFSF13B, CX3CR1, CD52, CCR1, ABHD2, MARCH1, LILRB2, PCDHGA12, SLC7A11,TLR4, GCNT1, AQP1, CALHM2, C3AR1, TRPM8, NRP1, SLC6A6, HAVCR2, POPDC3,IFNGR1, PTPRO, FADS3, GBP3, C4ORF34, NRCAM, UGCG, ADAMDEC1, KMO, ITGB5,ICAM1, GCNT1, ATP1B1, GLIPR1, IL10RA, SLC37A2, CD180, SLC43A2, NRP2,ST3GAL5, ATP9A, GLIPR1, CD36, TMEM39A, ADORA3, DSE, PCDH7, STEAP1,TMEM158, LPAR6, SLC41A2, LOC100131909, AQP1, CALHM2, NRP1, SLAMF8,ABCC3, TM7SF4, SLC7A11, TNFRSF21, PLA2G4A, LPCAT2, TNFSF13B, ABHD2,TBXAS1, MCOLN3, THBD, TLR4, SUCNR1, P2RY14, KMO, CLEC7A, ENPP2, LFNG,ABCB1, EMP1, GDPD1, EPS8, IL7R, CD52, PARM1, PTAFR, CNIH3, CD86, IL27RA,CXCR7, IL2RG, SLAMF8, ANKH, MMP14, GPR183, ABHD2, CKLF, C4ORF34,SLC41A2, HAVCR2, ALCAM, TLR4, GPR35, ITGB7, ADORA3, THBD, SLC41A2, OLR1,MCOLN3, CD36, TREM1, ALCAM GO: 0044421~extracellular THBD, CD44, FN1,FN1, MMP2, VEGFA, ANXA2P1, region part MMP19, CCL5, ANXA2P1, FN1,TNFSF13B, CD109, IL10, FGL2, MMP9, HMCN1, VEGFA, MMP14, CCL24, CD109,VEGFA, MMP1, CKLF, GNLY, HMOX1, COL6A1, A2M, ADAMTS15, ANXA2P2, CCL5,VEGFA, ANXA2P1, SERPINE2, TNFSF13B, THBD, IGFBP3, THBD, GPC1, FGL2,GNLY, COL22A1, CCL5, VASH1, IGFBP3, ICAM1, FN1 GO: 0004888~transmembraneTHBD, IL10RA, NRP1, CD36, ADORA3, IFNGR1, TLR4, receptor activity NRP2,IL7R, CX3CR1, CCR1, PTAFR, IL7R, CD36, IL27RA, IL2RG, CXCR7, ADORA3,HMCN1, TLR4, GPR183, IFNGR1, LPAR6, C3AR1, LOC100131909, EMR2, NRP1,NRP1, GPR35, TLR4, PTPRO, IFNGR1, ADORA3, THBD, CSF1R, CXCR7, THBD,TLR4, SUCNR1, OLR1, CD36, P2RY14, ENPP2, CD36, ICAM1 GO: 0006955~immuneFTHL3, OAS1, VEGFA, OAS1, CCL5, TLR4, CD180, response SLAMF7, IL7R,TNFSF13B, CCR1, PTAFR, IL7R, CD86, IL27RA, IL2RG, IL10, LILRB2, VEGFA,TLR4, CCL24, NOD2, GPR183, VEGFA, GBP5, GBP2, CCL5, VEGFA, TLR4, CYBB,LILRB1, TNFSF13B, PTX3, GBP3, TLR4, OLR1, P2RY14, CLEC7A, CCL5, ENPP2,TREM1, GBP2, ICAM1, TRIM22 GO: 0009611~response FN1, CD44, NRP1, CD36,ADORA3, CD180, CD36 to wounding ADORA3, ABHD2, HMOX1, NRP1, CYBB, ABHD2,PTX3, ABHD2, TLR4, THBD, CD36, CLEC7A, CD9, PAPSS2, FN1, THBD, FN1,ABHD2, CCL5, TLR4, FN1, CX3CR1, CCR1, PTAFR, ABHD2, IL10, MGLL, HMCN1,CCL24, ABHD2, TLR4, IRF7, INA, C3AR1, A2M, NRP1, CCL5, NLRC4, TLR4,THBD, ADORA3, OLR1, CCL5, CD36 GO: 0009605~response CD44, FN1, NRP1,CD36, ADORA3, CD180, NRP2, CD36, to external stimulus ADORA3, CDKN1A,NOD2, ABHD2, HMOX1, LOC100131909, NRP1, CYBB, PLA2G4A, PTX3, ABHD2,ABHD2, TLR4, THBD, CD36, CLEC7A, ENPP2, PAPSS2, CD9, FN1, THBD, FN1,ABHD2, CCL5, TLR4, FN1, CX3CR1, CCR1, PTAFR, ABHD2, IL10, MGLL, HMCN1,MMP14, IRF7, CCL24, ABHD2, TLR4, CKLF, INA, C3AR1, A2M, NRP1, CCL5,NLRC4, TLR4, ADORA3, THBD, CCND1, OLR1, CCL5, CD36 GO: 0002376~immuneOAS1, OAS1, CD180, SLAMF7, IL7R, MMP9, NOD2, system process EPAS1, GBP2,ID2, TM7SF4, CYBB, LILRB1, TNFSF13B, BCL6, PTX3, IFI30, TLR4, P2RY14,CLEC7A, ENPP2, GBP2, TRIM22, FTHL3, VEGFA, CCL5, ID2, TLR4, IL7R,TNFSF13B, CCR1, PTAFR, CD86, IL27RA, IL2RG, IL10, LILRB2, VEGFA, CCL24,GPR183, TLR4, VEGFA, GBP5, CKLF, C3AR1, BCL6, CCL5, VEGFA, TLR4, CRIP2,ID2, GBP3, OLR1, CCL5, TREM1, ICAM1 GO: 0050896~response FN1, CD44,OAS1, NRP1, CD36, CYP1B1, ADORA3, to stimulus SLAMF7, IL7R, EEPD1,CDKN1A, IFNGR1, ABHD2, ID2, CYBB, LILRB1, BCL6, ABHD2, GNLY, CD36, CD9,PAPSS2, ATP1B1, GBP2, PLIN2, TRIM22, PTGS1, FTHL3, THBD, VEGFA, ABHD2,IFNGR1, CCL5, TLR4, ID2, FN1, TNFSF138, CX3CR1, ME1, CCR1, ABHD2, IL10,LILRB2, HMCN1, SLC7A11, AQP1, CCL24, TLR4, IRF7, GBP5, C3AR1, RASGRF1,TRPM8, A2M, ME1, NRP1, VEGFA, IFNGR1, PTGS1, GBP3, EEPD1, HIPK2, KMO,ICAM1, ATP1B1, MMP2, OAS1, FGD4, CD180, NRP2, CYP1B1, CD36, ADORA3,NOD2, EPAS1, GNLY, LOC100131909, HMOX1, CYP1B1, AQP1, IFI44, GBP2, NRP1,SLC7A11, PLA2G4A, PTX3, TNFSF13B, ABHD2, MCOLN3, TLR4, THBD, P2RY14,KMO, CLEC7A, ENPP2, ABCB1, PTGS1, FN1, FN1, EPS8, IL7R, HSPB7, PTAFR,CD86, IL27RA, IL2RG, MGLL, VEGFA, ANKH, MMP14, ABHD2, GPR183, VEGFA,CKLF, INA, BCL6, FABP4, CCL5, NLRC4, CYP1B1, FGD4, TLR4, ID2, THBD,ADORA3, CCND1, OLR1, MCOLN3, CCL5, CD36, TREM1 GO:00322501~multicellular ADAP2, PAQR5, CD44, NRP1, CD36, CYP1B1, LBH,IL7R, organismal process KCNQ3, MMP9, PAQR5, MAF, GLDN, CDKN1A, MPZL3,PDLIM7, ID2, ANXA2P1, TFAP2A, ATF5, MITF, BCL6, CSF1R, CKB, CD36, NGEF,CD9, PAPSS2, IGFBP3, PTGS1, THBD, CSPG4, VEGFA, TLR4, ID2, PRDM1,SLC12A6, TRPS1, STATH, IL10, HMCN1, MAFB, AQP1, TLR4, C3AR1, RASGRF1,TRPM8, NRP1, VEGFA, SKIL, PTGS1, NRCAM, ARI05B, UGCG, HIPK2, MMP2,TRPS1, NRP2, CYP1B1, DAB2, CD36, EVL, ZFP36L1, NOD2, EPAS1, TUBB2A,LOC100131909, HMOX1, CYP1B1, AQP1, DAB2, ATF5, ANXA2P2, NRP1, TM7SF4,CDK5RAP2, PLA2G4A, SERPINE2, IGFBP3, LMNA, MCOLN3, TLR4, THBD, CLEC7A,LFNG, TRPS1, AHNAK, PGA5, EMP1, PTGS1, ANXA2P1, MMP19, NGEF, ANXA2P1,EPS8, DIXDC1, IL7R, TPRS1, MAFB, PTAFR, MITF, NPTX1, VEGFA, ANKH, MMP14,GPR183, MMP1, VEGFA, INA, BCL6, MDGA1, PDLIM7, ALCAM, FABP4, CDK5RAP2,NLRC4, CYP1B1, TLR4, CRIP2, ID2, THBD, CCND1, DAB2, ADAP2, OLR1, MCOLN3,DAB2, CD36, ALCAM GO: 0050793~regulation FN1, NRP1, CD36, FGD4, IL7R,CD36, ATP10A, MAF, of developmental PDLIM7, HMOX1, LOC100131909, ATF5,ID2, NRP1, process CDK5RAP2, ATF5, MITF, PLA2G4A, BCL6, IGFBP3, FGD2,TLR4, CD36, IGFBP3, FN1, FN1, VEGFA, FGD2, CCL5, ID2, TLR4, FN1, IL7R,MAFB, MITF, CD86, STATH, IL27RA, IL2RG, IL10, VEGFA, ANKH, MAFB, TLR4,VEGFA, BCL6, PDLIM7, CDK5RAP2, NRP1, CCL5, VEGFA, FGD4, FGD2, TLR4, ID2,FGD2, CCND1, NRCAM, CCL5, VASH1, CD36 GO: 0009897~external CD44, TRPM8,CSPG4, ALCAM, CD244, TLR4, TLR4, IL7R, side of plasma IL7R, NRCAM, CD86,IL2RG, TLR4, GPC1, CLEC7A, TLR4, membrane ALCAM, ICAM1 GO:0051239~regulation NRP1, ADORA3, IL7R, ADORA3, MAF, NOD2, EPAS1, ofmulticellular PDLIM7, HMOX1, LOC100131909, ATF5, ANXA2P2, ID2,organismal process NRP1, ANXA2P1, CDK5RAP2, ATF5, MITF, PLA2G4A, BCL6,IGFBP3, TLR4, CLEC7A, PTGS1, IGFBP3, PTGS1, VEGFA, ANXA2P1, CCL5, ID2,ANXA2P1, TLR4, IL7R, HSPB7, MAFB, MITF, CD86, STATH, IL27RA, IL2RG,IL10, VEGFA, ANKH, MAFB, TLR4, VEGFA, RASGRF1, BCL6, PDLIM7, CDK5RAP2,NRP1, CCL5, VEGFA, TLR4, ID2, PTGS1, ADORA3, NRCAM, CCND1, CCL5, VASH1GO: 0006952~defense CD44, FN1, FN1, ADORA3, CCL5, TLR4, CD180, FN1,response SLAMF7, CX3CR1, CCR1, PTAFR, IL27RA, ADORA3, IL10, MGLL,LILRB2, IRF7, TLR4, CCL24, NOD2, GNLY, C3AR1, HMOX1, LOC100131909, A2M,CCL5, NLRC4, TLR4, CYBB, PTX3, ADORA3, OLR1, TLR4, GNLY, CLEC7A, CCL5,FN1 GO: 0006954~inflammatory FN1, FN1, CD44, ADORA3, CCL5, CD180, TLR4,FN1, response CCR1, PTAFR, MGLL, ADORA3, IL10, TLR4, CCL24, IRF7, C3AR1,HMOX1, A2M, CCL5, NLRC4, TLR4, CYBB, PTX3, ADORA3, TLR4, OLR1, CLEC7A,CCL5, FN1 GO: 0031012~extracellular CD44, FN1, FN1, MMP2, COLGA1, VEGFA,ANXA2P1, matrix MMP19, ANXA2P2, ADAMTS15, VEGFA, ANXA2P1, ANXA2P1, FN1,GPC1, COL22A1, MMP9, HMCN1, VEGFA, MMP14, VEGFA, MMP1, FN1 GO:0048583~regulation NT5E, VEGFA, ANXA2P1, FGD4, CCL5, ANXA2P1, TLR4, ofresponse to stimulus IL7R, TMFSF13B, IL7B, CD86, IL27RA, IL10, VEGFA,NOD2, TLR4, IRF7, VEGFA, NT5E, C3AR1, HMOX1, LOC100131909, BCL6, A2M,FABP4, ANXA2P2, CCL5, VEGFA, FGD4, AMXA2P1, TLR4, PLA2G4A, TNFSF138,BCL6, TLR4, HIPK2, CLEC7A, CCL5, ICAM1 GO: 0005578~proteinaceous FN1,FN1, MMP2, COL6A1, VEGFA, ANXA2P1, MMP19, extracellular matrix ANXA2P2,ADAMTS15, VEGFA, ANXA2P1, ANXA2P1, FN1, GPC1, COL22A1, MMP9, HMCN1,VEGFA, MMP14, VEGFA, MMP1, FN1 GO: 0009986~cell surface CD44, CSPG4,VEGFA, CD36, TLR4, IL7R, IL7R, CD36, CD86, IL2RG, VEGFA, NOD2, TLR4,VEGFA, TRPM8, ALCAM, CD244, VEGFA, TM7SF4, TLR4, NRCAM, TLR4, GPC1,CD36, CLEC7A, CD36, ABCB1, ALCAM, ICAM1 GO: 0002682~regulation CD44,VEGFA, CCL5, ID2, TLR4, IL7R, TNFSF13B, MAFB, of immune system IL7R,MITF, CD86, IL27RA, IL2RG, IL10, VEGFA, CDKN1A, process MAFB, NOD2,TLR4, VEGFA, C3AR1, HMOX1, LOC100131909, BCL6, A2M, CCL5, VEGFA, ID2,TLR4, MITF, TNFSF13B, ID2, BCL6, TLR4, CLEC7A, CCL5, ICAM1 GO:0005615~extracellular THBD, FN1, FN1, MMP2, VEGFA, CCL5, FN1, TNFSF13B,space CD109, IL10, FGL2, MMP9, VEGFA, CD109, CCL24, VEGFA, CKLF, GNLY,HMOX1, A2M, CCL5, VEGFA, SERPINE2, TNFSF13B, IGFBP3, THBD, THBD, GPC1,GNLY, FGL2, CCL5, VASH1, IGFBP3, ICAM1, FN1 GO: 0048731~system ADAP2,CD44, MMP2, NRP1, TRPS1, NRP2, IL7R, EVL, development ZFP36L1, MAF,MMP9, CDKN1A, GLDN, EPAS1, TUBB2A, PDLIM7, HMOX1, ATF5, ANXA2P2, ID2,NRP1, ANXA2P1, TM7SF4, CDXSRAP2, ATF5, TFAP2A, PLA2G4A, MITF, SERPINE2,BCL6, IGFBP3, LMNA, MCOLN3, CKB, LFNG, NGEF, PAPSS2, CD9, TRPS1, AHNAK,IGFBP3, EMP1, ANXA2P1, CSPG4, VEGFA, MMP19, NGEF, ID2, ANXA2P1, PRDM1,IL7R, TRPS1, MAFB, MITF, STATH, TRPS1, NPTX1, IL10, MMP14, ANKH, MAFB,VEGFA, GPR183, VEGFA, INA, RASGRF1, BCL6, MDGA1, PDLIM7, ALCAM,CDK5RAP2, NRP1, VEGFA, CRIP2, ID2, NRCAM, CCND1, ARIDSB, UGCG, ADAP2,MCOLN3, ALCAM GO: 0051707~response THBD, CCL5, IFNGR1, TLR4, PTAFR,IL27RA, IL10, TLR4, to other organism NOD2, IRF7, IFNGR1, GNLY, IFI44,CCL5, NLRC4, TLR4, IFNGR1, LILRB1, PLA2G4A, PTX3, THBD, TLR4, THBD,GNLY, CLEC7A, CCL5, TRIM22 GO: 0007275~multicellular PAQR5, ADAP2, CD44,MMP2, NRP1, TRPS1, LBH, NRP2, organismal DAB2, IL7R, EVL, ZFP36L1, MAF,PAQR5, MMP9, development CDKN1A, GLDN, EPAS1, TUBB2A, PDLIM7, HMOX1,DAB2, ATF5, ANXA2P2, ID2, NRP1, ANXA2P1, TM7SF4, CDK5RAP2, ATF5, TFAP2A,PLA2G4A, MITF, SERPINE2, BCL6, IGFBP3, CSF1R, LMNA, MCOLN3, CKB, THBD,LFNG, NGEF, PAPSS2, CD9, TRPS1, AHNAK, IGFBP3, EMP1, THBD, VEGFA,ANXA2P1, CSPG4, MMP19, NGEF, ID2, ANXA2P1, PRDM1, DIXDC1, IL7R, TRPS1,MAFB, MITF, STATH, TRPS1, NPTX1, IL10, MMP14, ANKH, VEGFA, MAFB, GPR183,VEGFA, INA, RASGRF1, BCL6, MDGA1, PDLIM7, ALCAM, CDK5RAP2, NRP1, VEGFA,CRIP2, SKIL, ID2, THBD, NRCAM, CCND1, ARID5B, UGCG, DAB2, ADAP2, HIPK2,MCOLN3, DAB2, ALCAM GO: 0032101~regulation NT5E, LOC100131909, BCL6,VEGFA, ANXA2P1, A2M, of response to external FABP4, ANXA2P2, CCL5, CCL5,VEGFA, TLR4, ANXA2P1, stimulus AMXA2P1, TLR4, PLA2G4A, BCL6, TLR4, IL10,VEGFA, CCL5, TLR4, VEGFA, NT5E GO: 0022610~biological CD44, FN1, FN1,NRP1, CD36, CCL5, FN1, SLAMF7, adhesion MTSS1, NRP2, PCDHGA12, CX3CR1,CCR1, CD36, PCDHGA12, RAPH1, PCDH7, MPZL3, COL6A1, ALCAM, CCL5, NRP1,RAPH1, NRP1, MTSS1, ITGB7, LPXN, NRCAM, OLR1, CD36, CLEC7A, COL22A1,CCL5, CD36, ITGB5, CD9, ALCAM, ICAM1, FN1 GO: 0007155~cell CD44, FN1,FN1, NRP1, CD36, CCL5, FN1, SLAMF7, adhesion MTSS1, NRP2, PCDHGA12,CX3CR1, CCR1, CD36, PCDHGA12, RAPH1, PCDH7, MPZL3, COL6A1, ALCAM, CCL5,NRP1, RAPH1, NRP1, MTSS1, ITG87, LPXN, NRCAM, OLR1, CD36, CLEC7A,COL22A1, CCL5, CD36, ITGB5, CD9, ALCAM, ICAM1, FN1 GO:0048856~anatomical ADAP2, FN1, CD44, MMP2, NRP1, TRPS1, NRP2, DAB2,structure development IL7R, EVL, ZFP36L1, MAF, MMP9, CDKN1A, GLDN,EPAS1, TUB82A, PDLIM7, HMOX1, DAB2, ATF5, ANXA2P2, ID2, NRP1, ANXA2P1,TM7SF4, CDK5RAP2, ATF5, TFAP2A, PLA2G4A, MITF, SERPINE2, BCL6, IGFBP3,LMNA, MCOLN3, CKB, LFNG, NGEF, PAPSS2, CD9, TRPS1, AHNAX, IGFBP3, EMP1,FN1, FN1, ANXA2P1, CSPG4, VEGFA, MMP19, HGEF, ID2, ANXA2P1, PRDM1, FN1,IL7B, TRPS1, MAFB, MITF, STATH, TRPS1, NPTX1, IL10, MMP14, ANKH, MAFB,VEGFA, GPR183, VEGFA, INA, RASGRF1, BCL6, MDGA1, PDLIM7, ALCAM,CDK5RAP2, NRP1, VEGFA, CRIP2, ID2, NRCAM, CCND1, ARID5B, UGCG, DAB2,ADAP2, MCOLN3, DAB2, ALCAM GO: 0065008~regulation MFI2, FN1, NRP1, CD36,CYP1B1, FGD4, IL7R, DAB2, of biological quality CYP1B1, CD36, ATP10A,CDKN1A, EPAS1, HMOX1, LOC100131909, CYP181, DAB2, ANXA2P2, ID2, NRP1,ANXA2P1, PLA2G4A, TNFSF13B, BCL6, CKB, FGD2, THBD, TLR4, IFI30, CD36,PAPSS2, CD9, FTGS1, EMP1, PTGS1, FN1, FTHL3, THBD, FN1, VEGFA, ANXA2P1,FGD2, CCL5, TLR4, ID2, ANXA2P1, FN1, SLC12A6, IL7R, TNFSF13B, CD52,CD52, CCR1, STATH, IL10, HMCN1, VEGFA, IRF7, TLR4, VEGFA, C3AR1,RASGRF1, BCL6, TRPM8, FABP4, CCL5, NRP1, VEGFA, CYP1B1, FGD4, FGD2,TLR4, ID2, THBD, PTGS1, FGD2, DAB2, CCL5, CD36, DAB2, SERTAD1 GO:0007166~cell surface NRP1, ADORA3, MTSS1, MAML3, IL7R, EVL, ADORA3,receptor linked signal MAML2, LPAR6, LOC100131909, EMR2, NRP1, MAML2,transduction MITF, CSF1R, CXCR7, SUCNR1, P2RY14, CLEC7A, ENPP2, VEGFA,CCL5, MAML2, EPS8, DIXDC1, IL7R, CK3CR1, CCR1, PTAFR, MITF, IL27RA,CXCR7, LILRB2, VEGFA, GPR183, VEGFA, MAML2, C3AR1, MAML2, NRP1, CCL5,VEGFA, DOK2, MTSS1, GPR35, ITGB7, ADORA3, CCND1, ARID5B, RGS13,ADAMDEC1, HIPK2, CCL5, ITGB5 GO: 0050727~regulation NT5E, BCL6,LOC100131909, A2M, FABP4, CCL5, CCL5, of inflammatory TLR4, TLR4,PLA2G4A, BCL6, TLR4, IL10, CCL5, TLR4, response NT5E GO:0006950~response FN1, CD44, MMP2, NRP1, CD36, FGD4, ADORA3, CD180, tostress SLAMF7, CD36, ADORA3, CDKN1A, EEPD1, NOD2, EPA51, GNLY, ABHD2,HMOX1, LOC100131909, NRP1, CYBB, PLA2G4A, BCL6, ABHD2, PTX3, ABHD2,TLR4, THBD, GNLY, CD36, KMO, CLEC7A, CD9, PAPSS2, ATP1B1, PTGS1, FN1,PTGS1, THBD, FN1, VEGFA, ABHD2, CCL5, TLR4, FN1, HSPB7, CX3CR1, CCR1,PTAFR, ABHD2, IL27RA, MGU, IL10, LILRB2, HMCN1, MMP14, VEGFA, CCL24,ABHD2, TLR4, IRF7, VEGFA, INA, C3AR1, BCL6, TRPM8, A2M, NRP1, CCL5,NLRC4, FGD4, VEGFA, TLR4, PTGS1, THBD, ADORA3, CCND1, OLR1, EEPD1,HIPK2, KMO, CCL5, CD36, ATP1B1 GO: 0032502~developmental ADAP2, PAQR5,CD44, FN1, NRP1, LBH, IL7R, MMP9, process PAQRS, MAF, GLDN, CDKN1A,PDLIM7, ID2, ANXA2P1, TFAP2A, ATF5, MITF, BCL6, CSF1R, CKB, NGEF, CD9,PAPSS2, IGFBP3, PTGS1, THBD, CSPG4, VEGFA, CCL5, ID2, FN1, PRDM1, TRPS1,STATH, IL10, MAFB, RASGRF1, NRP1, VEGFA, SKIL, PTGS1, ARID5B, NRCAM,UGCG, HIPK2, MMP2, TRPS1, NRP2, DAB2, EVL, ZFP36L1, EPAS1, TUBB2A,HMOX1, DAB2, ATFS, ANXA2P2, NRP1, TM7SF4, CDK5RAP2, SERPINE2, PLA2G4A,IGFBP3, LMNA, MCOLN3, THBD, LFNG, TRPS1, AHNAK, EMP1, PTGS1, FN1, FN1,ANXA2P1, MMP19, NGEF, ANXA2P1, DIXDC1, IL7R, TRPS1, MAFB, MITF, NPTX1,VEGFA, ANKH, MMP14, GPR183, VEGFA, INA, BCL6, MDGA1, PDLIM7, ALCAM,FABP4, CDK5RAP2, CCL5, CRIP2, ID2, THBD, CCND1, ADAP2, DAB2, MCOLN3,CCL5, DAB2, ALCAM GO: 0031347~regulation NT5E, LOC10013I909, BCL6, A2M,FABP4, CCL5, CCL5, of defense response TLR4, TLR4, PLA2G4A, BCL6, TLR4,IL10, CLEC7A, CCL5, TLR4, IRF7, NOD2, NT5E GO: 0009607~response THBD,CCL5, IFNGR1, TLR4, HSPB7, PTAFR, IL27RA, IL10, to biotic stimulus TLR4,NOD2, IRF7, IFNGR1, GNLY, IFI44, CCL5, NLRC4, IFNGR1, TLR4, LILRB1,PLA2G4A, PTX3, THBD, CCND1, TLR4, THBD, GNLY, CLEC7A, CCL5, TRIM22 GO:0019955~cytokine IL10RA, CD36, A2M, IFNGR1, IL7R, IFNGR1, CX3CR1,binding CCR1, IL7R, CSF1R, CD36, IL27RA, IL2RG, CD36, CD36, IFNGR1 GO:0050776~regulation C3AR1, HMOX1, LOC100131909, BCL6, A2M, TLR4, ofimmune response TLR4, IL7R, TNFSF138, TNFSF138, BCL6, IL7R, CD86,IL27RA, TLR4, IL10, CLEC7A, NOD2, TLR4, ICAM1 GO: 0040011~locomotionFN1, FN1, CD44, NRP1, CCLS, FN1, NRP2, CX3CR1, S100A2, CCR1, PTAFR,IL10, MMP14, CCL24, CKLF, C3AR1, MDGA1, CCL5, NRP1, NRP1, ARID58, NRCAM,CCL5, ENPP2, ICAM1, FN1 GO: 0080134~regulation NTSE, ANXA2P1, FGD4,CCLS, ANXA2P1, TLR4, IL10, of response to stress NOD2, TLR4, IRF7, NT5E,BCL6, LOC100131909, A2M, FABP4, ANXA2P2, CCL5, FGD4, ANXA2P1, TLR4,PLA2G4A, BCL6, TLR4, HIPK2, CLEC7A, CCL5 GO: 0007626~locomotory C3AR1,CCL5, CCL5, EPS8, NRP2, CX3CR1, CCR1, PTAFR, behavior MCOLN3, HIPK2,IL10, MCOLN3, ANKH, CCL5, ENPP2, CCL24, CKLF GO: 0002684~positive C3AR1,LOC100131909, BCL6, VEGFA, VEGFA, TLR4, regulation of immune IL7R, TLR4,TNFSF13B, TNFSF13B, BCL6, IL7R, CD86, system process IL27RA, IL2RG,TLR4, CLEC7A, VEGFA, CDKN1A, NOD2, TLR4, VEGFA, ICAM1 GO: 0000267~cellNT5E, OAS1, CD36, CYP1B1, OAS1, SYTL1, PCDHGA12, fraction NRP2, RAB38,CYP1B1, CD36, PTRF, NTSE, HMOX1, CYP1B1, FADS3, ANXA2P1, ABCC3, PLA2G4A,TNFSF13B, TBXAS1, PTRF, LMNA, CD36, ABCB1, EMP1, PTGS1, PTGS1, ANXA2P1,CCL5, ANXA2P1, EPS8, SLC12A6, TNFSF13B, ME1, CD52, CD52, PSD3, LILRB2,PCDHGA12, RASGRF1, ME1, FABP4, CCL5, CYP1B1, PTGS1, FADS3, UGCG, OLR1,CTSL1, CCL5, CD36, PSD3 GO: 0045028~purinergic LPAR6, LOC100131909,SUCNR1, P2RY14, ADORA3, nudeotide receptor ADORA3, GPR183, ADORA3activity, G-protein coupled GO: 0001608~nucleotide LPAR6, LOC100131909,SUCNR1, P2RY14, ADORA3, receptor activity, G- ADORA3, GPR183, ADORA3protein coupled GO: 0004930~G-protein LPAR6, C3AR1, LOC100131909, EMR2,ADORA3, GPR35, coupled receptor activity CX3CR1, CCR1, PTAFR, ADORA3,CXCR7, CXCR7, SUCNR1, P2RY14, ADORA3, GPR183 GO: 0016502~nucleotideLPAR6, LOC100131909, SUCNR1, P2RY14, ADORA3, receptor activity ADORA3,GPR183, ADORA3 GO: 0001614~purinergic LPAR6, LOC100131909, SUCNR1,P2RY14, ADORA3, nucleotide receptor ADORA3, GPR183, ADORA3 GO:0005626~insoluble NT5E, OAS1, CD36, OAS1, CYP1B1, EPS8, SLC12A6,friction NRP2, SYTL1, PCDHGA12, CD52, CD52, RAB38, CYP1B1, PSD3, CD36,ULRB2, PCDHGA12, PTRF, NT5E, RASGRF1, HMOX1, CYP1B1, CYP1B1, FADS3,ABCC3, PLA2G4A, PTRF, TBXAS1, PTGS1, FADS3, LMNA, UGCG, OLR1, CD36,CD36, PSD3, ABCB1, PTGS1, EMP1, PTGS1 GO: 0048513~organ ADAP2, CD44,MMP2, NRP1, NRP2, IL7R, EVL, ZFP36L1, development MMP9, MAF, CDKN1A,EPAS1, HMOX1, ANXA2P2, NRP1, ID2, ANXA2P1, TM7SF4, CDK5RAP2, TFAP2A,MITF, PLA2G4A, BCL6, LMNA, MCOLN3, CKB, LFNG, EMP1, ANXA2P1, CSPG4,VEGFA, MMP19, ANXA2P1, ID2, PRDM1, IL7R, MAFB, MITF, STATH, IL10, VEGFA,MMP14, MAFB, GPR183, VEGFA, INA, BCL6, MDGA1, CDKSRAP2, NRP1, VEGFA,CRIP2, ID2, CCND1, ARID5B, UGCG, ADAP2, MCOLN3 GO: 0002697~regulationIL7R, HMOX1, LOC100131909, BCL6, IL27RA, A2M, IL10, of immune effectorNOD2, IL7R, ICAM1, BCL6 process GO: 0051384~response CCND1, A2M, FABP4,IL10, CCL5, CCL5, CDKN1A, CCL5, to glucocorticoid PTGS1, PLA2G4A, PTGS1,PTGS1 stimulus GO: 0005624~membrane NT5E, OAS1, CD36, OAS1, CYP1B1,EPS8, SLC12A6, fraction NRP2, SYTL1, PCDHGA12, CD52, CD52, RAB38,CYP1B1, PSD3, CD36, LILRB2, PCDHGA12, PTRF, NT5E, RASGRF1, HMOX1,CYP1B1, CYP1B1, FADS3, ABCC3, PLA2G4A, PTRF, TBXAS1, PTGS1, FADS3, UGCG,OLR1, CD36, CD36, PSD3, ABCB1, PTG51, EMP1, PTGS1 hsa04060:Cytokine-TNFRSF21, IL10RA, VEGFA, IFNGR1, CCL5, CCL5, VEGFA, cytokine receptorIFNGR1, IL7R, TNFSF13B, TNFRSF21, CX3CR1, TNFSF13B, interaction CCR1,CSF1R, IL7R, IL2RG, IL10, VEGFA, CCL5, CCL24, VEGFA, IFNGR1 GO:0031349~positive LOC100131909, FABP4, CCL5, CCL5, TLR4, TLR4, regulationof defense PLA2G4A, TLR4, CLEC7A, CCL5, TLR4, IRF7, NOD2 response GO:0048584~positive C3AR1, LOC100131909, VEGFA, FABP4, CCL5, CCL5,regulation of response to VEGFA, TLR4, TLR4, TNFSF13B, PLA2G4A,TNFSF13B, stimulus IL27RA, TLR4, HIPK2, CLEC7A, VEGFA, CCL5, NOD2, TLR4,IRF7, VEGFA GO: 0031960~response CCND1, A2M, FABP4, IL10, CCL5, CCL5,CDKN1A, CCL5, to corticosteroid PTGS1, PLA2G4A, PTGS1, PTGS1 stimulusGO: 0042221~response CD44, MMP2, CYP1B1, NRP2, CYP1B1, CDKN1A, NOD2, tochemical stimulus EPAS1, HMOX1, AQP1, CYP1B1, ID2, SLC7A11, PLA2G4A,TLR4, THBD, CLEC7A, ENPP2, ATP1B1, ABCB1, PTGS1, PLIN2, PTGS1, THBD,VEGFA, CCL5, ID2, TLR4, EPS8, HSPB7, ME1, CX3CR1, CCR1, PTAFR, IL10,SLC7A11, VEGFA, MMP14, AQP1, CCL24, TLR4, VEGFA, CKLF, C3AR1, A2M, ME1,FABP4, CCL5, VEGFA, CYP1B1, TLR4, ID2, PTGS1, THBD, CCND1, OLR1, CCL5,ATP1B1 GO: 0065007~biological TCF4, NT5E, MFI2, NRP1, ADORA3, SLAMF7,RAB38, regulation IL7R, PDK4, MAF, PHLDA1, MAML2, ARHGAP18, CD244, ID2,ANXA2P1, RAB7B, RIN2, ATF5, TFAP2A, MITF, BCL6, ABHD2, CSF1R, CKB, FGL2,TCF4, CD36, IGFBP3, PTGS1, FTHL3, HIVEP1, TNFRSF21, ABHD2, CCL5, ID2,PRDM1, FN1, TNFSF13B, TCF4, CX3CR1, CCR1, TRPS1, STATH, IL10, HMCN1,MAFB, TCF4, RASGRF1, A2M, FGD2, CYTIP, IFNGR1, SKIL, PHLDA1, LPXN,PTSS1, FGD2, NRCAM, ADAMDEC1, ICAM1, FGD4, MAML3, CYP1B1, DAPP1, CD36,ZFP36L1, ARHGAP18, PTRF, NOD2, EPAS1, ARHGAP18, HMOX1, LOC100131909,ANXA2P2, NRP1, CDK5RAP2, TNFRSF21, PLA2G4A, SERPINE2, TNFSF13B, IGFBP3,PTRF, FGD2, SUCNR1, THBO, P2RY14, CLEC7A, TRPS1, PTGS1, ARHGEF3, NGEF,ANXA2P1, IL7R, HSPB7, TRPS1, CD52, MITF, CD86, IL27RA, CKCR7, FGL2,VEGFA, RAPH1, VEGFA, MAML2, BCL6, MAML2, PDLIM7, ALCAM, FABP4, RAPH1,FGD4, GPR35, ID2, RGS13, ADAP2, DAB2, DAB2, ALCAM, ADAP2, FN1, CD44,CD36, CYP1B1, LBH, MTSS1, PHLDA1, AGPAT9, MMP9, DDIT4L, ATP10A, CDKN1A,IFNGR1, PDLIM7, ABHD2, EMR2, RGL1, TCF4, RAB7B, CXCR7, IFI30, APBB1IP,NGEF, CD9, PAPSS2, TRIM22, THBD, VEGFA, CSPG4, IFNGR1, MAML2, TLR4,SLC12A6, CDS2, C9ORF89, ABHD2, PSD3, CCL24, TLR4, IRF7, C3AR1, TRPM8,NRP1, VEGFA, ARID5B, TCF4, HIPK2, APBB1IP, VASH1, PSD3, TRPS1, DAB2,ADORA3, SNAI3, APBB1IP, NT5E, LPAR6, CYP1B1, DAB2, ATF5, MAML2, PTX3,ABHD2, TLR4, ENPP2, GLIS3, EMP1, BCL2A1, FN1, FN1, ANXA2P1, FGD2,RAB27B, EPS8, MAFB, PTAFR, CNIH3, IL2RG, PDK4, MMP14, ANKH, GPR183,ABHD2, ARHGAP20, CDX5RAP2, CCL5, NLRC4, CYP1B1, MTSS1, DOK2, TLR4,CRIP2, THBD, ADORA3, CCND1, CCL5, CD36, CHD9, TREM1, SERTAD1 GO:0050865~regulation HMOX1, BCL6, LOC100131909, TLR4, TLR4, IL7R, of cellactivation TNFSF13B, TNFSF13B, BCL6, IL7R, CD86, IL27RA, TLR4, IL2RG,IL10, CDKN1A, TLR4 GO: 0048545~response HMOX1, AQP1, FABP4, A2M, CCL5,CCL5, PIA2G4A, to steroid hormone PTGS1, CCND1, IL10, CCL5, MMP14,CDKN1A, AQP1, stimulus PTGS1, PTGS1 GO: 0006935~chemotaxis C3AR1, IL10,CCL5, CCL5, CCL5, ENPP2, CCL24, NRP2, CKLF, CX3CR1, CCR1, PTAFR GO:0042330~taxis C3AR1, IL10, CCL5, CCL5, CCL5, ENPP2, CCL24, NRP2, CKLF,CX3CR1, CCR1, PTAFR GO: 0002703~regulation IL7R, HMOX1, LOC100131909,BCL5, IL27RA, IL10, of leukocyte mediated NOD2, IL7R, BCL6 immunity GO:0002822~regulation IL7R, BCL6, CD86, IL27RA, IL10, NOD2, IL7R, TNFSF13B,of adaptive immune TNFSF13B, BCL6 response based on somaticrecombination of immune receptors built from immunoglobulin superfamilydomains G0: 0001568~blood CD44, HMOX1, MMP2, CSPG4, NRP1, ANXA2P1,VEGFA, vessel development MMP19, ANXA2P2, NRP1, NRP1, ANXA2P1, VEGFA,ANXA2P1, NRP2, ZFP36L1, MMP14, VEGFA, VEGFA, EPAS1 G0: 0030154~cellPAQR5, FN1, CD44, NRP1, NRP2, IL7R, DAB2, ZFP36L1, differentiationPAQR5, MMP9, MAF, GLDN, TUBB2A, EPAS1, PDLIM7, DAB2, ATF5, NRP1, ID2,TM7SF4, CDK5RAP2, ATF5, MITF, SERPINE2, BCL6, IGFBP3, MCOLN3, NGEF,IGFBP3, EMP1, FN1, FN1, VEGFA, CSPG4, MMP19, NGEF, ID2, FN1, PRDM1,IL7R, MITF, IL10, VEGFA, MMP14, GPR183, VEGFA, INA, RASGRF1, BCL6,MDGA1, ALCAM, PDLIM7, FABP4, CDK5RAP2, NRP1, VEGFA, ID2, NRCAM, CCND1,DAB2, MCOLN3, DAB2, ALCAM GO: 0001944~vasculature CD44, HMOX1, MMP2,CSPG4, NRP1, ANXA2P1, VEGFA, development MMP19, ANXA2P2, NRP1, NRP1,ANXA2P1, VEGFA, ANXA2P1, NRP2, ZFP36L1, MMP14, VEGFA, VEGFA, EPAS1 G0:0002819~regulation IL7R, BCL6, CD86, IL27RA, IL10, NOD2, IL7R, TNFSF13B,of adaptive immune TNFSF13B, BCL6 response GO: 0051241~negative HMOX1,BCL6, LOC100131909, ANXA2P1, VEGFA, regulation of ANXA2P2, ANXA2P1,VEGFA, ANXA2P1, BCLS, STATH, multicellular organismal IL10, VEGFA, N0D2,VEGFA GO: 0051704~multi- THBD, IFNGR1, CCL5, TLR4, CX3CR1, PTAFR, CD86,organism process IL27RA, IL2RG, CXCR7, IL10, IRF7, NOD2, TLR4, MMP1,IFNGR1, GNLY, IFI44, CCL5, NLRC4, IFNGR1, TLR4, LILRB1, PLA2G4A, PTX3,THBD, CXCR7, TLR4, THBD, HIPK2, GNLY, CLE7A, CCL5, ICAM1, TRIM22 GO:0007165~signal NRP1, CD36, FGD4, ADORA3, MTSS1, RAB38, DAPP1,transduction IL7R, CD36, PDK4, ADORA3, ARHGAP18, NOD2, EPAS1, APB81IP,IFNGR1, ARHGAP18, LPAR6, HMOX1, LOC100131909, EMR2, ARHGAP18, RGL1,CD244, NRP1, RAB7B, RIN2, THFRSF21, RAB7B, TNFSF138, CSF1R, CXCR7,SUCNR1, TLR4, FGL2, P2RY14, CD36, CLEC7A, APBB1IP, TNFRSF21, CSPG4,ARHGEF3, IFNGR1, CCL5, RAB27B, TLR4, EPS8, IL7R, TNFSF138, CX3CR1, CCR1,PTAFR, CNIH3, IL2RG, CXCR7, PDK4, IL10, FGL2, RAPH1, CCL24, GPR183,TLR4, C3AR1, ARHGAP20, RASGRF1, ALCAM, NRP1, CCL5, RAPH1, FGD4, DOK2,MTSS1, GPR35, IFHGR1, TLR4, LPXN, ADORA3, CCND1, HIPK2, APBB1IP, CCL5,CD36, TREM1, ALCAM GO: 0009617~response THBD, CCL5, CCL5, NLRC4, TLR4,TLR4, PLA2G4A, THBD, to bacterium PTAFR, IL27RA, TLR4, THBD, IL10, GNLY,CCL5, NOD2, TLR4, GNLY GO: 0048519~negative TCF4, NT5E, NRP1, TRPS1,IL7R, DAB2, DDIT4L, CDKN1A, regulation of biological NOD2, NT5E, ABHD2,HMOX1, LOC100131909, DAB2, process ATF5, ANXA2P2, ID2, NRP1, TCF4,ANXA2P1, ATF5, MITF, TNFSF13B, BCL6, ABHD2, ABHD2, IGFBP3, TLR4, IFI30,TCF4, TRPS1, GLIS3, CD9, PTGS1, IGFBP3, BCL2A1, FTGS1, FTHL3, HIVEP1,VEGFA, ANXA2P1, ABHD2, CCL5, TLR4, ANXA2P1, ID2, PRDM1, IL7R, TNFSF13B,TCF4, C9ORF89, TRF51, MAFB, ABHD2, MITF, IL27RA, TRPS1, STATH, IL10,VEGFA, MMP14, MAFB, IRF7, TLR4, ABHD2, VEGFA, TCF4, BCLG, FABP4, A2M,CCL5, NRP1, VEGFA, TLR4, SKIL, ID2, PTGS1, ARID5B, CCND1, RGS13, DAB2,TCF4, ADAMDEC1, HIPK2, CCL5, VASH1, DAB2, SERTAD1 GO: 0050864~regulationBCL6, IL27RA, IL2RG, IL10, CDKN1A, TNFSF13B, of B cell activationTNFSF13B, BCL6 GO: 0001525~angiogenesis HMOX1, CSPG4, ANXA2P1, VEGFA,NRP1, MMP19, ANXA2P2, NRP1, ANXA2P1, VEGFA, NRP1, ANXA2P1, NRP2, MMP14,VEGFA, VEGFA, EPAS1 GO: 0048869~cellular PAQR5, FN1, CD44, NRP1, NRP2,IL7R, DAB2, ZFP36L1, developments process PAQR5, MMP9, MAF, GLDN,TUBB2A, EPAS1, PDLIM7, DAB2, ATF5, NRP1, ID2, TM7SF4, CDK5RAP2, ATF5,MITF, SERPINE2, BCL6, IGFBP3, MCOLN3, CD9, NGEF, IGFBP3, EMP1, FN1, FN1,VEGFA, CSPG4, MMP19, NGEF, ID2, FN1, PRDM1, IL7R, MITF, IL10, VEGFA,MMP14, GPR183, VEGFA, INA, RASGRF1, BCL6, MDGA1, ALCAM, PDLIM7, FABP4,CDKSRAP2, NRP1, VEGFA, ID2, NRCAM, CCND1, DAB2, MCOLN3, DAB2, ALCAM GO:0002694~regulation BCL6, LOC100131909, HMOX1, IL7R, TNFSF13B, BCL6, ofleukocyte activation TNFSF13B, IL7R, CD86, IL27RA, IL2RG, IL10, CDKN1AGO: 0044243~multicellular MMP2, MMP19, MMP9, MMP1 organismal catabolicprocess GO: 0030574~collagen MMP2, MMP19, MMP9, MMP1 cataboltc processGO: 0016477~cell FN1, FN1, CD44, MDGA1, NRP1, NRP1, CCL5, CCL5,migration NRP1, FN1, NRP2, S100A2, NRCAM, ABID5B, IL10, MMP14, CCL5,CKLF, ICAM1, FN1 GO: 0045595~regulation NRP1, CD36, CCL5, ID2, TLR4,IL7R, MAFB, IL7R, MITF, of cell differentiation CD36, CD86, IL2RG, MAF,MAFB, TLR4, PDLIM7, BCL6, PDLIM7, ATF5, CDK5RAP2, NRP1, CCL5, NRP1, ID2,TLR4, CDK5RAP2, ATF5, MITF, BCL6, ID2, IGFBP3, NRCAM, CCND1, TLR4, CD36,CCL5, CD36, IGFBP3 GO: 0032879~regulation NRP1, VEGFA, CD36, ABHD2,RAB27B, ABHD2, CD36, of localization IL10, MMP9, VEGFA, ABHD2, NOD2,VEGFA, ABHD2, HMOX1, BCL6, LOC100131909, NRP1, NRP1, VEGFA, SERPINE2,PLA2G4A, ABHD2, BCL6, PTX3, IGFBP3, ABHD2, PTGS1, CD36, CLEC7A, ENPP2,VASH1, CD36, IGFBP3, PTGS1, ICAM1, PTGS1 GO: 0050729~positiveLOC100131909, TLR4, FABP4, CCL5, CCL5, TLR4, CCL5, regulation of TLR4,TLR4, PLA2G4A inflammatory response GO: 0007186~G-protein LPAR6, C3AR1,LOC100131909, EMR2, ADORA3, CCL5, coupled receptor protein CCL5, GPR35,CX3CR1, CCR1, ADORA3, PTAFR, CXCR7, signaling pathway RGS13, CXCR7,SUCNR1, ADORA3, P2RY14, CCL5, ENPP2, GPR183 GO: 0051270~regulationABHD2, HMOX1, BCL6, MRP1, VEGFA, ABHD2, MRP1, of cell motion NRP1,VEGFA, SERPINE2, BCL6, ABHD2, IGFBP3, ABHD2, ABHD2, MMP9, VEGFA, ENPP2,VASH1, ABHD2, VEGFA, IGFBP3, ICAM1 GO: 0048518~positive TCF4, CD44,NRP1, CD36, FGD4, SLAMF7, MAML3, IL7R, regulation of biological CD36,PHLDA1, PHLDA1, MAF, MMP9, CDKN1A, NOD2, process MAML2, EPAS1, PDUM7,LOC100131909, HMOX1, ID2, NRP1, TCF4, MAML2, PLA2G4A, MITF, BCL6, PTX3,TNFSF138, IGFBP3, FGD2, TLR4, TCF4, CD36, CLEC7A, HGEF, GUS3, PTGS1,IGFBP3, PTGS1, VEGFA, ARHGEF3, FGD2, NGEF, CCL5, ID2, MAML2, TLR4,PRDM1, IL7R, TNFSF13B, TCF4, MAFB, MITF, CD86, IL27RA, IL2RG, IL10,MAFB, VEGFA, TLR4, IRF7, VEGFA, MAML2, TCF4, C3AR1, RASGRF1, BCL6,PDUM7, MAML2, FABP4, NRP1, CCL5, NLRC4, FGD4, VEGFA, FGD2, TLR4, CRIP2,PHLDA1, ID2, PTGS1, FGD2, NRCAM, CCND1, TCF4, HIPK2, CCL5, CD36, ICAM1,SERTAD1 GO: 001816~cytokine TLB4, FABP4, NLRC4, MAF, TLR4, NOD2, TLR4,TLR4, production PTAFR GO: 0007610~behavior C3AR1, RASGRF1, CCL5, CCL5,EPS8, NRP2, CX3CR1, CCR1, PTAFR, MCOLN3, HIPK2, IL10, MCOLN3, ANKH,CCL5, ENPP2, CCL24, CKLF GO: 00550878~regulation THBD, ANXA2P1, CD36,ANXA2P2, ANXA2P1, ANXA2P1, of body fluid levels THBD, CD36, STATH, THBD,CD36, HMCN1, CD36, CD9, PAPSS2 GO: 0032496~response THBO, CCL5, CCL5,TLR4, TLR4, PLA2G4A, THBD, PTAFR, to lipopolysaccharide TLR4, THBD,IL10, CCL5, TLR4, NOD2 GO: 0002683~negative IL7R, HMOX1, BCL6, IL27RA,A2M, IL10, NOD2, IL7R, regulation of immune BCL6 GO:0051674~localization FN1, FN1, CD44, MDGA1, NRP1, NRP1, CCL5, CCL5, ofcell NRP1, FN1, NRP2, S100A2, NRCAM, ARID5B, IL10, MMP14, CCL5, CKLF,ICAM1, FN1 GO: 0048870~cell motility FN1, FN1, CD44, MDGA1, NRP1, NRP1,CCL5, CCL5, NRP1, FN1, NRP2, S100A2, NRCAM, ARID5B, IL10, MMP14, CCL5,CKLF, ICAM1, FN1 GO: 0046903~secretion HMOX1, LOC100131909, AQP1,ANKA2P1, DAB2, ANXA2P2, CCL5, CCL5, ANXA2P1, NLRC4, ANXA2P1, SYTL1,TNFSF138B, TNFSF13B, DAB2, STATH, DAS2, CCL5, AQP1, DAB2, CKLF GO:0006928~cell motion FN1, FN1, CD44, NRP1, CCL5, FN1, MTSS1, NRP2,S100A2, IL10, MMP14, CKLF, MDGA1, ALCAM, CCL5, NRP1, NRP1, MTSS1,ARID5B, NRCAM, CCL5, ENPP2, CD9, ALCAM, ICAM1, FN1 GO: 0048514~bloodHMOX1, CSPG4, ANXA2P1, VEGFA, NRP1, MMP19, vessel morphogenesis ANXA2P2,NRP1, NRP1, ANXA2P1, VEGFA, ANXA2P1, NRP2, ZFP36L1, MMP14, VEGFA, VEGFA,EPAS1 GO: 0001501~skeletal MMP2, ANXA2P1, PDLIM7, ANXA2P1, ANXA2P1,TRPS1, system development TFAP2A, TRPS1, IGFBP3, ARID5B, STATH, TRPS1,MMP9, MMP14, ANKH, TRPS1, PAPSS2, IGFBP3, PDLIM7 GO: 0050867~positiveBCL6, LOC100131909, TLR4, TLR4, IL7R, TNFSF13B, regulation of cellTNFSF13B, BCL6, IL7R, CD86, TLR4, IL2RG, CDKN1A, activation TLR4 GO:0030247~polysaccharide CD44, FN1, FN1, VEGFA, VEGFA, FN1, SERPINE2,PTX3, binding CLEC7A, VEGFA, NOD2, ENPP2, VEGFA, FN1 GO: 0001871~patternCD44, FN1, FN1, VEGFA, VEGFA, FN1, SERPINE2, PTX3, binding CLEC7A,VEGFA, NOD2, ENPP2, VEGFA, FN1 GO: 0004222~metalloendopeptidase MMP2,ADAMDEC1, MMP19, ADAMTS15, MMP9, activity MMP14, MMP1 GO:0002698~negative IL7R, HMOX1, BCL6, A2M, IL7R, BCL6 regulation of immuneeffector process GO: 0002698~positive LOC100131909, VEGFA, FABP4, CCL5,CCL5, TLR4, regulation of response to VEGFA, TLR4, PLA2G4A, TLR4, CCL5,VEGFA, TLR4, external stimulus VEGFA GO: 0010033~response THBD, CD44,CYP1B1, CCL5, ID2, TLR4, EPS8, HSPB7, to organic substance ME1, PTAFR,CYP1B1, IL10, MMP14, CDKN1A, AQP1, NOD2, TLR4, HMOX1, AQP1, CYP1B1, A2M,ME1, FABP4, CCL5, CYP1B1, ID2, TLR84, PLA2G4A, ID2, THBD, PTGS1, CCND1,THBD, TLR4, CLEC7A, CCL5, PTGS1, PLIN2, PTGS1

TABLE 6 Human monocyte study: pathways significantly enriched amonggenes upregulated by Probioglat relative to Copaxone ® at 6 hours.Pathways significantly enriched among genes upregulated by Probioglatrelative to GA (mannitol-corrected comparison) at 6 hours: Fold TermPvalue Enrichment Benjamini Probesets Genes GO:0005576~extracellular1.59E−09 4.042562158 2.49E−07 213503_X_AT, 210427_X_AT, ANXA2P1,ANXA2P1, CD40, PLAUR, CD40, GHRL, region 205153_S_AT, 214866_AT, IL7R,GLIPR1, CCL2, STATH, IL10, FGL2, MMP9, 215346_AT, 223862_AT, 226218_AT,MMP1, ADAM9, COL6A1, CD14, ANXA2P2, 226142_AT, 216598_S_AT, SRPX2,ANXA2P1, TNFSF13B, PTX3, EGF, 206835_AT, 207433_AT, 227265_AT, ANTXR2,THBD, ADAMDEC1, ICAM1, CCL5, 203936_S_AT, 204475_AT, TREM1, ICAM1202381_AT, 213428_S_AT, 201743_AT, 208816_X_AT, 205499_AT 201590_X_AT,223502_S_AT, 206157_AT, 206254_AT, 228573_AT, 203887_S_AT, 206134_AT,202637_S_AT, 1555759_A_AT, 215434_AT, 202638_S_AT GO:0002376~immune1.04E−08 4.156626506 1.53E−05 209933_S_AT, 210017_AT, CD300A, MALT1,CD40, CD40, NFKBIA, VPS33A, system process 205153_S_AT, 215346_AT, IL7R,CCL2, IL10, MMP9, SOD2, GPR183, NOD2, 201502_S_AT, 204590_X_AT, CD55,KYNU, CD55, SOD2, ADAM9, CD14, 226218_AT, 216598_S_AT, TNFSF13B, PTX3,SOD2, ICAM1, IFIH1, CCL5, 207433_AT, 203936_S_AT, 221477_S_AT, MLF1,KYNU, TREM1, ICAM1 205419_AT, 220066_AT, 201926_S_AT, 217388_S_AT,1555950_A_AT, 215223_S_AT, 202381_AT, 201743_AT, 223502_S_AT, 206157_AT,216841_S_AT, 202637_S_AT, 219209_AT, 1555759_A_AT, 204784_S_AT,210663_S_AT, 219434_AT, 202638_S_AT GO:0048583~regulation of 1.56E−075.897095846 0.000115129 213503_X_AT, 210017_AT, ANXA2P1, MALT1, FABP4,ANXA2P2, ANXA2P1, response to stimulus 203980_AT, 208816_X_AT, CD40,NFKBIA, ANXA2P1, CD40, GHRL, IL7R, 210427_X_AT, 205153_S_AT, THFSF13B,IL10, ICAM1, CCL5, NOD2, CD55, 201502_S_AT, 201590_X_AT, NT5E, CD55,ICAM1 215346_AT, 223862_AT, 226218_AT, 223502_S_AT, 207433_AT,202637_S_AT, 1555759_A_AT, 220066_AT, 201926_S_AT, 203939_AT,1555950_A_AT, 202638_S_AT GO:0044421~extracellular 2.87E−06 4.6644947970.000225327 213428_S_AT, 202381_AT, COL6A1, ADAM9, ANXA2P1, ANXA2P2,region part 213503_X_AT, 208816_X_AT, ANXA2P1, ANXA2P1, GHRL, CCL2,TNFSF13B, 210427_X_AT, 201590_X_AT, EGF, THBD, IL10, ICAM1, FGL2, MMP9,CCL5, 223862_AT, 216598_S_AT, MMP1, ICAM1 223502_S_AT, 206254_AT,203887_S_AT, 207433_AT, 202637_S_AT, 227265_AT, 203936_S_AT,1555759_A_AT, 204475_AT, 202638_S_AT GO:0048519~negative 6.21E−072.625285194 0.000305261 213891_S_AT, 203927_AT, TCF4, NFKBIE, ANXA2P1,MALT1, ANXA2P1, regulation of biological 213503_X_AT, 210017_AT, P2RX4,NFKBIA, PRDM1, GHRL, IL7R, TCF4, process 210427_X_AT, 204088_AT,201502_S_AT, CCL2, MAFB, DAB2, STATH, IL10, NOD2, SOD2, 228964_AT,223862_AT, NT5E, ARL6IP5, BIRC3, SOD2, TNFRSF9, ARL6IP5, 226218_AT,212387_AT, 216598_S_AT, FABP4, ANXA2P2, ANXA2P1, CHST11, MITF,218559_S_AT, 201278_AT, THFSF13B, EGF, SOD2, TNFAIP3, ADAMDEC1,206835_AT, 207433_AT, 220066_AT, CCL5, CD9 221477_S_AT, 203939_AT,200761_S_AT, 210538_S_AT, 215223_S_AT, 207536_S_AT, 200760_S_AT,203980_AT, 208816_X_AT, 201590_X_AT, 219634_AT, 226066_AT, 223502_S_AT,206254_AT, 216841_S_AT, 202644_S_AT, 206134_AT, 1555759_A_AT, 201005_ATGO:0006955~immune 1.10E−06 4.644030668 0.000325195 209933_S_AT,210017_AT, 201743_AT, CD300A, MALT1, CD14, IL7R, CCL2, TNFSF13B,response 226218_AT, 216598_S_AT, PTX3, IFIH1, ICAMl, IL10, CCL5, NOD2,GPR183, 223502_S_AT, 206157_AT, 219209_AT, KYNU, CD55, KYNU, TREM1,CD55, ICAM1 202637_S_AT, 207433_AT, 1555759_A_AT, 220066_AT, 205419_AT,210663_S_AT, 201926_S_AT, 217388_S_AT, 219434_AT, 1555950_A_AT,202638_S_AT GO:0002237~response to 1.01E−06 14.53261321 0.000370434203887_S_AT, 210017_AT, 201743_AT, THBD, MALT1, CD14, IL10, NFKBIA,CCL5, NOD2, molecule of bacterial origin 207433_AT, 201502_S_AT, CCL21555759_A_AT, 220066_AT, 216598_S_AT GO:0005886~plasma 7.17E−062.132725656 0.000375322 219358_S_AT, 204912_AT, ADAP2, IL10RA, CD300A,ANXA2P1, CD36, membrane 209933_S_AT, 213503_X_AT, ANXA2P1, P2RX4, FXYD2,CD40, PLAUR, CD40, 209555_S_AT, 210427_X_AT, VPS33A, IL7R, SNX20, SYNJ2,SYNJ2, GPR183, 204088_AT, 207434_S_AT, NOD2, CD55, NT5E, CD55, STEAP1,LPAR6, 205153_S_AT, 214866_AT, 215346_AT, ADAM9, COL6A1, TNFRSF9, CD14,ANXA2P2, 204590_X_AT, 226218_AT, ANXA2P1, IFNGR1, TNFSF13B, SNX20, EGF,229045_AT, 216180_S_AT, 212828_AT, ANTXR2, THBD, ICAM1, PLEKHO1, GPR34,205419_AT, 220066_AT, ITGB5, CD9, TREM1, ICAM1 201926_S_AT, 203939_AT,1555950_A_AT, 205542_AT, 218589_AT, 202381_AT, 213428_S_AT, 207536_S_AT,201743_AT, 208816_X_AT, 201590_X_AT, 211676_S_AT, 223502_S_AT,228869_AT, 206254_AT, 228573_AT, 203887_S_AT, 202637_S_AT, 218223_S_AT,244434_AT, 201125_S_AT, 201005_AT, 219434_AT, 202638_S_ATGO:0051707~response to 2.07E−06 7.289156627 0.000507682 203887_S_AT,210017_AT, 201743_AT, THBD, MALT1, CD14, IFIH1, IL10, NFKBIA, CCL5,other organism 219209_AT, 207433_AT, NOD2, IFNGR1, CCL2, PTX3201502_S_AT, 1555759_A_AT, 220066_AT, 211676_S_AT, 216598_S_AT,206157_AT GO:0050878~regulation of 2.72E−06 12.58047114 0.000572071206835_AT, 213503_X_AT, STATH, ANXA2P1, CD36, THBD, ANXA2P2, body fluidlevels 209555_S_AT, 203887_S_AT, ANXA2P1, CD40, PLAUR, ANXA2P1, CD40,CD9 208816_X_AT, 210427_X_AT, 205153_S_AT, 214866_AT, 201590_X_AT,215346_AT, 201005_AT GO:0032879~regulation of 3.74E−06 4.528429020.000688621 202381_AT, 203927_AT, 209555_S_AT, ADAM9, NFKBIE, CD36,ARL6IP5, RAB27B, localization 200760_S_AT, 228708_AT, P2RX4, CD40,NFKBIA, CD40, GHRL, PTX3, EGF, 204088_AT, 205153_S_AT, 201502_S_AT,IL10, ICAM1, MMP9, NOD2, ARL6IP5, ICAM1 215346_AT, 223862_AT, 206157_AT,206254_AT, 207433_AT, 202637_S_AT, 203936_S_AT, 220066_AT, 200761_S_AT,202638_S_AT GO:0032496~response to 6.46E−06 14.75060241 0.000865084203887_S_AT, 201743_AT, THBD, CD14, IL10, NFKBIA, CCL5, NOD2, CCL2lipopolysaccharide 207433_AT, 201502_S_AT, 1555759_A_AT, 220066_AT,216598_S_AT GO:0060089~molecular 5.73E−06 2.807496252 0.000876051204912_AT, 209933_S_AT, 209555_S_AT, IL10RA, CD300A, CD36, MALT1, P2RX4,CD40, transducer activity 210017_AT, 204088_AT, CD40, PLAUR, GHRL, IL7R,CCL2, GPR183, 205153_S_AT, 215346_AT, 214866_AT, LPAR6, TNFRSF9, CD14,SRA1, IFNGR1, EGF, 223862_AT, 226218_AT, ANTXR2, THBD, ICAM1, CCL5,ITGB5, GPR34, 216598_S_AT, 205419_AT, 218589_AT, TREM1, ICAM1207536_S_AT, 201743_AT, 224130_S_AT, 211676_S_AT, 206254_AT, 228573_AT,203887_S_AT, 202637_S_AT, 1555759_A_AT, 201125_S_AT, 244434_AT,219434_AT, 202638_S_AT GO:004871~signal 5.73E−06 2.807496252 0.000876051204912_AT, 209933_S_AT, 209555_S_AT, IL10RA, CD300A, CD36, MALT1, P2RX4,CD40, transducer activity 210017_AT, 204088_AT, CD40, PLAUR, GHRL, IL7R,CCL2, GPR183, 205153_S_AT, 215346_AT, 214866_AT, LPAR6, TNFRSF9, CD14,SRA1, IFNGR1, EGF, 223862_AT, 226218_AT, ANTXR2, THBD, ICAM1, CCL5,ITGB5, GPR34, 216598_S_AT, 205419_AT, 218589_AT, TREM1, ICAM1207536_S_AT, 201743_AT, 224130_S_AT, 211676_S_AT, 206254_AT, 228573_AT,203887_S_AT, 202637_S_AT, 1555759_A_AT, 201125_S_AT, 244434_AT,219434_AT, 202638_S_AT GO:0065007~biological 5.36E−06 1.4773583540.000877763 219358_S_AT, 213891_S_AT, ADAP2, TCF4, CD36, MALT1, P2RX4,NFE2L3, regulation 209555_S_AT, 210017_AT, NFKBIA, VPS33A, DAB2, AGPAT9,MMP9, SOD2, 204088_AT, 236471_AT, 201502_S_AT, NOD2, NT5E, CD55,ARHGAP18, BIRC3, SOD2, 204590_X_AT, 201278_AT, LPAR6, ADAM9, TNFRSF9,ARL6IP5, ARHGAP18, 224480_S_AT, 203936_S_AT, ANXA2P2, BID, ANXA2P1,NFE2L3, CHST11, 221477_S_AT, 220066_AT, MITF, PTX3, TNFSF13B, EGF, MXD1,SOD2, 203939_AT, 1555950_A_AT, THBD, TNFAIP3, CD9, BID, GLRX3, NFKBIE,225166_AT, 210538_S_AT, ANXA2P1, RAB27B, CD40, ANXA2P1, PLAUR,215223_S_AT, 218589_AT, PRDM1, CD40, GHRL, IL7R, CCL2, TCF4, MAFB,202381_AT, 207536_S_AT, HNRPLL, BID, STATH, IL10, FGL2, GPR183, CD55,200760_S_AT, 225171_AT, ARL6IP5, FABP4, CD14, TNFAIP6, SRA1, MTSS1,208816_X_AT, 211725_S_AT, CYTIP, IFNGR1, CAST, LPXN, ADAMDEC1, IFIH1,201590_X_AT, 204702_S_AT, 219634_AT, ICAM1, CCL5, GPR34, TREM1, ICAM1226066_AT, 206157_AT, 223502_S_AT, 206254_AT, 226275_AT, 216841_S_AT,203887_S_AT, 202644_S_AT, 201005_AT, 204493_AT, 209080_X_AT, 203927_AT,213503_X_AT, 228708_AT, 205153_S_AT, 210427_X_AT, 214866_AT, 228964_AT,215346_AT, 223862_AT, 226218_AT, 216598_S_AT, 212387_AT, 218559_S_AT,225386_S_AT, 227143_S_AT, 206835_AT, 207433_AT, 227265_AT, 205419_AT,201926_S_AT, 200761_S_AT, 203980_AT, 201743_AT, 206026_S_AT,224130_S_AT, 203037_S_AT, 209606_AT, 211676_S_AT, 208908_S_AT,216250_S_AT, 206134_AT, 219209_AT, 202637_S_AT, 1555759_A_AT, 244434_AT,219434_AT, 202638_S_AT GO:0065008~regulation of 6.39E−06 2.8712242330.000941783 203927_AT, 213503_X_AT, NFKBIE, ANXA2P1, CD36, P2RX4,ANXA2P1, biological quality 209555_S_AT, 204088_AT, CD40, NFKBIA, CD40,PLAUR, GHRL, IL7R, CCL2, 210427_X_AT, 205153_S_AT, BID, DAB2, STATH,IL10, SOD2, CD55, CD55, 201502_S_AT, 215346_AT, SOD2, FABP4, ANXA2P2,BID, ANXA2P1, 214866_AT, 223862_AT, 226218_AT, TNFSF13B, SOD2, THBD,CCL5, CD9, BID, GLRX3 216598_S_AT, 227143_S_AT, 201278_AT, 206835_AT,207433_AT, 221477_S_AT, 201926_S_AT, 1555950_A_AT, 215223_S_AT,203980_AT, 208816_X_AT, 211725_S_AT, 201590_X_AT, 223502_S_AT,216841_S_AT, 203887_S_AT, 1555759_A_AT, 201005_AT, 204493_AT,209080_X_AT GO:0050789~regulation of 7.87E−06 1.49362031 0.000966198219358_S_AT, 213891_S_AT, ADAP2, TCF4, CD36, MALT1, P2RX4, NFE2L3,biological process 209555_S_AT, 210017_AT, NFKBIA, VPS33A, DAB2, AGPAT9,MMP9, SOD2, 204088_AT, 236471_AT, 201502_S_AT, NOD2, NT5E, CD55,ARHGAP18, BIRC3, SOD2, 204590_X_AT, 201278_AT, LPAR6, ADAM9, TNFRSF9,ARL6IP5, ARHGAP18, 224480_S_AT, 203936_S_AT, ANXA2P2, BID, ANXA2P1,NFE2L3, CHST11, 221477_S_AT, 220066_AT, MITF, PTX3, TNFSF13B, EGF, MXD1,SOD2, 203939_AT, 1555950_A_AT, TNFAIP3, CD9, BID, GLRX3, NFKBIE,ANXA2P1, 225166_AT, 210538_S_AT, RAB27B, CD40, ANXA2P1, PLAUR, PRDM1,215223_S_AT, 218589_AT, CD40, GHRL, IL7R, CCL2, TCF4, MAFB, HNRPLL,202381_AT, 207536_S_AT, BID, STATH, IL10, FGL2, GPR183, CD55, ARL6IP5,200760_S_AT, 225171_AT, FABP4, CD14, TNFAIP6, SRA1, MTSS1, CYTIP,208816_X_AT, 211725_S_AT, IFNGR1, LPXN, ADAMDEC1, IFIH1, ICAM1, CCL5,201590_X_AT, 204702_S_AT, 219634_AT, GPR34, TREM1, ICAM1 226066_AT,206157_AT, 223502_S_AT, 206254_AT, 226275_AT, 216841_S_AT, 202644_S_AT,201005_AT, 204493_AT, 209080_X_AT, 203927_AT, 213503_X_AT, 228708_AT,205153_S_AT, 210427_X_AT, 214866_AT, 228964_AT, 215346_AT, 223862_AT,226218_AT, 216598_S_AT, 212387_AT, 218559_S_AT, 225386_S_AT,227143_S_AT, 206835_AT, 207433_AT, 227265_AT, 205419_AT, 201926_S_AT,200761_S_AT, 203980_AT, 201743_AT, 206026_S_AT, 224130_S_AT,203037_S_AT, 209606_AT, 211676_S_AT, 216250_S_AT, 206134_AT, 219209_AT,202637_S_AT, 1555759_A_AT, 244434_AT, 219434_AT, 202638_S_ATGO:0051049~regulation of 8.87E−06 5.49711891 0.00100533 203927_AT,202381_AT, 200760_S_AT, NFKBIE, ADAM9, ARL6IP5, RAB27B, CD40, transport228708_AT, 205153_S_AT, P2RX4, CD40, NFKBIA, GHRL, PTX3, EGF, IL10,204088_AT, 215346_AT, 201502_S_AT, NOD2, ARL6IP5 223862_AT, 206157_AT,206254_AT, 207433_AT, 220066_AT, 200761_S_AT GO:0004872~receptor4.04E−06 3.357899833 0.001236866 218589_AT, 204912_AT, LPAR6, IL10RA,CD300A, TNFRSF9, CD36, CD14, activity 209933_S_AT, 207536_S_AT, P2RX4,CD40, PLAUR, SRA1, CD40, GHRL, 209555_S_AT, 201743_AT, 204088_AT,IFNGR1, IL7R, ANTXR2, THBD, ICAM1, GPR183, 205153_S_AT, 214866_AT,GPR34, ITGB5, TREM1, ICAM1 224130_S_AT, 215346_AT, 223862_AT,211676_S_AT, 226218_AT, 228573_AT, 203887_S_AT, 202637_S_AT, 205419_AT,244434_AT, 201125_S_AT, 219434_AT, 202638_S_AT GO:0009611~response to1.27E−05 4.789156627 0.001249473 215223_S_AT, 209555_S_AT, SOD2, CD36,CD14, CD40, CD40, TNFAIP6, wounding 201743_AT, 205153_S_AT, PLAUR, CCL2,PTX3, SOD2, THBD, 1L10, CCL5, 215346_AT, 206026_S_AT, 214866_AT, SOD2,CD9, CD55, CD55 216598_S_AT, 206157_AT, 216841_S_AT, 203887_S_AT,207433_AT, 1555759_A_AT, 221477_S_AT, 201005_AT, 201926_S_AT,1555950_A_AT hsa04060: Cytokine- 1.73E−05 6.212389381 0.001276815204912_AT, 207536_S_AT, 207433_AT, IL10RA, TNFRSF9, IL10, CD40, CD40,CCL5, cytokine receptor 205153_S_AT, 215346_AT, IFNGR1, IL7R, CCL2,TNFSF13B, EGF interaction 1555759_A_AT, 211676_S_AT, 226218_AT,216598_S_AT, 223502_S_AT, 206254_AT GO:0002682~regulation of 1.23E−055.312341804 0.001290482 210017_AT, 205153_S_AT, 215346_AT, MALT1, CD40,CD40, NFKBIA, IL7R, MITF, immune system process 201502_S_AT, 226218_AT,TNFSF13B, MAFB, IL10, ICAM1, CCL5, NOD2, 226066_AT, 223502_S_AT, CD55,CD55, ICAM1 218559_S_AT, 207433_AT, 202637_S_AT, 1555759_A_AT,220066_AT, 201926_S_AT, 1555950_A_AT, 202638_S_AT GO:0048518~positive1.62E−05 2.290466213 0.001326312 213891_S_AT, 209555_S_AT, TCF4, CD36,MALT1, P2RX4, CD40, NFKBIA, regulation of biological 210017_AT,204088_AT, CD40, PRDM1, GHRL, IL7R, TCF4, CCL2, MAFB, process205153_S_AT, 201502_S_AT, 215346_AT, HNRPLL, BID, IL10, MMP9, NOD2,SOD2, CD55, 228964_AT, 223862_AT, CD55, SOD2, ADAM9, TNFRSF9, FABP4,CD14, 226218_AT, 212387_AT, BID, SRA1, MITF, TNFSF13B, PTX3, EGF, SOD2,216598_S_AT, 218559_S_AT, ICAM1, CCL5, BID, ICAM1 225386_S_AT,227143_S_AT, 207433_AT, 203936_S_AT, 220066_AT, 221477_S_AT,201926_S_AT, 1555950_A_AT, 215223_S_AT, 202381_AT, 207536_S_AT,203980_AT, 201743_AT, 211725_S_AT, 224130_S_AT, 226066_AT, 223502_S_AT,206157_AT, 206254_AT, 216841_S_AT, 202637_S_AT, 1555759_A_AT, 204493_AT,202638_S_AT GO:0051239~regulation of 1.72E−05 3.498329255 0.001330564213503_X_AT, 210017_AT, 201743_AT, ANXA2P1, MALT1, CD14, ANXA2P2, P2RX4,multicellular organismal 208816_X_AT, 204088_AT, ANXA2P1, CD40, NFKBIA,ANXA2P1, CD40, process 210427_X_AT, 205153_S_AT, GHRL, IL7R, CCL2, MITF,MAFB, EGF, STATH, 201502_S_AT, 201590_X_AT, IL10, CCL5, NOD2 215346_AT,223862_AT, 226218_AT, 216598_S_AT, 226066_AT, 218559_S_AT, 206254_AT,206835_AT, 207433_AT, 1555759_A_AT, 220066_AT GO:0060341~regulation of1.61E−05 7.836801752 0.001398752 203927_AT, 202381_AT, 207433_AT,NFKBIE, ADAM9, IL10, RAB27B, CD40, NFKBIA, cellular localization228708_AT, 205153_S_AT, CD40, NOD2, GHRL, EGF 201502_S_AT, 215346_AT,220066_AT, 223862_AT, 206254_AT GO:0051046~regulation of 1.57E−059.688408808 0.001446037 202381_AT, 207433_AT, 228708_AT, ADAM9, IL10,RAB27B, P2RX4, CD40, CD40, secretion 204088_AT, 205153_S_AT, NOD2, GHRL,EGF 215346_AT, 220066_AT, 223862_AT, 206254_AT GO:0002822~regulation of3.26E−05 15.80421687 0.001846658 210017_AT, 207433_AT, 205153_S_AT,MALT1, IL10, CD40, CD40, NOD2, IL7R, adaptive immune response 215346_AT,220066_AT, TNFSF13B based on somatic 226218_AT, 223502_S_ATrecombination of immune receptors built from immunoglobulin superfamilydomains GO:0043067~regulation of 2.93E−05 3.182057087 0.001877378215223_S_AT, 202381_AT, 207536_S_AT, SOD2, ADAM9, TNFRSF9, MALT1, P2RX4,BID, programmed cell death 210017_AT, 204088_AT, NFKBIA, GHRL, CHST11,CCL2, MITF, TNFSF13B, 211725_S_AT, 201502_S_AT, BID, SOD2, TNFAIP3,IFIH1, IL10, MMP9, SOD2, 223862_AT, 219634_AT, NOD2, BID, BIRC3216598_S_AT, 226066_AT, 223502_S_AT, 227143_S_AT, 216841_S_AT,202644_S_AT, 219209_AT, 207433_AT, 203936_S_AT, 221477_S_AT, 220066_AT,204493_AT, 210538_S_AT GO:0010941~regulation of 3.06E−05 3.1714147560.001878077 215223_S_AT, 202381_AT, 207536_S_AT, SOD2, ADAM9, TNFRSF9,MALT1, P2RX4, BID, cell death 210017_AT, 204088_AT, NFKBIA, GHRL,CHST11, CCL2, MITF, TNFSF13B, 211725_S_AT, 201502_S_AT, BID, SOD2,TNFAIP3, IFIH1, IL10, MMP9, SOD2, 223862_AT, 219634_AT, NOD2, BID, BIRC3216598_S_AT, 226066_AT, 223502_S_AT, 227143_S_AT, 216841_S_AT,202644_S_AT, 219209_AT, 207433_AT, 203936_S_AT, 221477_S_AT, 220066_AT,204493_AT, 210538_S_AT GO:0009617~response to 3.20E−05 8.6896037760.001886839 203887_S_AT, 210017_AT, 201743_AT, THBD, MALT1, CD14, IL10,NFKBIA, CCL5, NOD2, bacterium 207433_AT, 201502_S_AT, CCL2 1555759_A_AT,220066_AT, 216598_S_AT GO:0042981~regulation of 2.57E−05 3.214416990.001895789 215223_S_AT, 202381_AT, 207536_S_AT, SOD2, ADAM9, TNFRSF9,MALT1, P2RX4, BID, apoptosis 210017_AT, 204088_AT, NFKBIA, GHRL, CHST11,CCL2, MITF, TNFSF13B, 211725_S_AT, 201502_S_AT, BID, SOD2, TNFAIP3,IFIH1, IL10, MMP9, SOD2, 223862_AT, 219634_AT, NOD2, BID, BIRC3216598_S_AT, 226066_AT, 223502_S_AT, 227143_S_AT, 216841_S_AT,202644_S_AT, 219209_AT, 207433_AT, 203936_S_AT, 221477_S_AT, 220066_AT,204493_AT, 210538_S_AT GO:0050776~regulation of 2.88E−05 7.2385726110.001926271 210017_AT, 202637_S_AT, MALT1, ICAM1, IL10, CD40, NFKBIA,CD40, immune response 207433_AT, 205153_S_AT, NOD2, CD55, IL7R,TNFSF13B, ICAM1, CD55 201502_S_AT, 215346_AT, 220066_AT, 201926_S_AT,226218_AT, 223502_S_AT, 202638_S_AT, 1555950_A_AT GO:0048513~organ2.80E−05 2.616968956 0.001962303 219358_S_AT, 213503_X_AT, ADAP2,ANXA2P1, MALT1, ANXA2P1, PRDM1, development 210017_AT, 210427_X_AT,PLAUR, GHRL, VPS33A, IL7R, CCL2, MAFB, 228964_AT, 214866_AT, 223862_AT,STATH, TGM5, IL10, MMP9, SOD2, GPR183, 204590_X_AT, 226218_AT, CRYBB2,SOD2, ADAM9, ANXA2P2, ANXA2P1, 216598_S_AT, 218559_S_AT, CHST11, MITF,EGF, SOD2, MLF1 206835_AT, 207911_S_AT, 207433_AT, 203936_S_AT,221477_S_AT, 205419_AT, 206777_S_AT, 215223_S_AT, 202381_AT,208816_X_AT, 201590_X_AT, 219634_AT, 226066_AT, 206254_AT, 216841_S_AT,204784_S_AT GO:0002819~regulation of 3.69E−05 15.41874816 0.002010277210017_AT, 207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, NOD2, IL7R,adaptive immune response 215346_AT, 220066_AT, TNFSF13B 226218_AT,223502_S_AT GO:0009605~response to 4.27E−05 3.433366869 0.002243592215223_S_AT, 209555_S_AT, SOD2, CD36, CD14, CD40, PLAUR, CD40, externalstimulus 201743_AT, 205153_S_AT, TNFAIP6, GHRL, CCL2, PTX3, SOD2, THBD,IL10, 214866_AT, 215346_AT, 206026_S_AT, CCL5, SOD2, NOD2, KYNU, CD9,CD55, KYNU, 223862_AT, 216598_S_AT, CD55 206157_AT, 216841_S_AT,203887_S_AT, 207433_AT, 1555759_A_AT, 221477_S_AT, 220066_AT,210663_S_AT, 201005_AT, 201926_S_AT, 217388_S_AT, 1555950_A_ATGO:0045428~regulation of 4.62E−05 23.94578313 0.002345211 215223_S_AT,216841_S_AT, SOD2, SOD2, ICAM1, IL10, P2RX4, SOD2, ICAM1, nitric oxidebiosynthetic 202637_S_AT, 207433_AT, PTX3 process 204088_AT,221477_S_AT, 202638_S_AT, 206157_AT GO:0051223~regulation of 5.39E−0510.2434739 0.002644616 203927_AT, 202381_AT, 207433_AT, NFKBIE, ADAM9,IL10, CD40, NFKBIA, CD40, protein transport 205153_S_AT, 201502_S_AT,NOD2, EGF 215346_AT, 220066_AT, 206254_AT GO:0009607~response to5.71E−05 4.995585791 0.002709622 203887_S_AT, 210017_AT, 201743_AT,THBD, MALT1, CD14, IFH1, IL10, NFKBIA, CCL5, biotic stimulus 219209_AT,207433_AT, NOD2, IFNGR1, CCL2, PTX3 201502_S_AT, 1555759_A_AT,220066_AT, 211676_S_AT, 216598_S_AT, 206157_AT GO:0005615~extracellular7.88E−05 4.831639194 0.00308733 202381_AT, 203887_S_AT, 202637_S_AT,ADAM9, THBD, ICAM1, IL10, FGL2, MMP9, space 207433_AT, 227265_AT, CCL5,GHRL, CCL2, TNFSF13B, ICAM1, EGF 203936_S_AT, 1555759_A_AT, 223862_AT,216598_S_AT, 223502_S_AT, 202638_S_AT, 206254_AT GO:0051241~negative7.32E−05 9.704343691 0.0033662 206835_AT, 213503_X_AT, 208816_X_AT,STATH, ANXA2P1, ANXA2P2, IL10, P2RX4, regulation of multicellular207433_AT, 204088_AT, ANXA2P1, ANXA2P1, NOD2, GHRL organismal process210427_X_AT, 201590_X_AT, 220066_AT, 223862_AT GO:0032101~regulation of8.47E−05 9.455514365 0.00366669 213503_X_AT, 203980_AT, ANXA2P1, FABP4,ANXA2P2, IL10, ANXA2P1, response to external 208816_X_AT, 207433_AT,ANXA2P1, CCL5, GHRL, NT5E stimulus 210427_X_AT, 201590_X_AT,1555759_A_AT, 223862_AT, 203939 AT GO:0070201~regulation of 8.47E−059.455514365 0.00366669 203927_AT, 202381_AT, 207433_AT, NFKBIE, ADAM9,IL10, CD40, NFKBIA, CD40, establishment of protein 205153_S_AT,201502_S_AT, NOD2, EGF localization 215346_AT, 220066_AT, 206254_ATGO:0050793~regulation of 8.33E−05 3.669304082 0.003713809 215223_S_AT,202381_AT, SOD2, ADAM9, CD36, CD40, NFKBIA, CD40, developmental process209555_S_AT, 205153_S_AT, GHRL, VPS33A, IL7R, MITF, MAFB, EGF, SOD2,201502_S_AT, 215346_AT, 223862_AT, STATH, IL10, CCL5, SOD2 204590_X_AT,226218_AT, 226066_AT, 218559_S_AT, 206254_AT, 216841_S_AT, 206835_AT,207433_AT, 1555759_A_AT, 221477_S_AT GO:0048522~positive 9.67E−052.22534329 0.00406592 213891_S_AT, 209555_S_AT, TCF4, CD36, MALT1,P2RX4, CD40, NFKBIA, regulation of cellular 210017_AT, 204088_AT, CD40,GHRL, IL7R, TCF4, CCL2, MAFB, HNRPLL, process 205153_S_AT, 201502_S_AT,215346_AT, BID, IL10, MMP9, NOD2, SOD2, SOD2, ADAM9, 223862_AT,226218_AT, TNFRSF9, FABP4, BID, SRA1, MITF, TNFSF13B, 212387_AT,216598_S_AT, EGF, PTX3, SOD2, ICAM1, CCL5, BID, ICAM1 218559_S_AT,225386_S_AT, 227143_S_AT, 207433_AT, 203936_S_AT, 220066_AT,221477_S_AT, 215223_S_AT, 202381_AT, 207536_S_AT, 203980_AT,211725_S_AT, 224130_S_AT, 226066_AT, 223502_S_AT, 206254_AT, 206157_AT,216841_S_AT, 202637_S_AT, 1555759_A_AT, 204493_AT, 202638_S_ATGO:0032501~multicellular 0.000104285 1.860570435 0.004260994219358_S_AT, 213503_X_AT, ADAP2, ANXA2P1, CD36, MALT1, ANXA2P1,organismal process 209555_S_AT, 210017_AT, P2RX4, CD40, PLAUR, PRDM1,CD40, VPS33A, 210427_X_AT, 204088_AT, 205153_S_AT, GHRL, IL7R, CCL2,MAFB, DAB2, STATH, TGM5, 214866_AT, 228964_AT, IL10, MMP9, GPR183, NOD2,SOD2, MMP1, 215346_AT, 204590_X_AT, 223862_AT, BIRC3, CRYBB2, SOD2,ADAM9, FABP4, 226218_AT, 216598_S_AT, ANXA2P2, ANXA2P1, CHST11, MITF,EGF, 218559_S_AT, 201278_AT, 206835_AT, AKR1C2, MXD1, SOD2, THBD, MLF1,CD9 207911_S_AT, 207433_AT, 203936_S_AT, 205419_AT, 220066_AT,221477_S_AT, 204475_AT, 210538_S_AT, 206777_S_AT, 215223_S_AT,202381_AT, 203980_AT, 208816_X_AT, 201590_X_AT, 219634_AT, 226066_AT,206254_AT, 211653_X_AT, 226275_AT, 216841_S_AT, 203887_S_AT,204784_S_AT, 201005_AT GO:0007166-cell surface 0.000113804 2.8561837710.004523702 218589_AT, 202381_AT, 210017_AT, LPAR6, ADAM9, MALT1, CD14,CD40, NFKBIA, receptor linked signal 201743_AT, 205153_S_AT, CD40, GHRL,MTSS1, IL7R, CCL2, MITF, EGF, transduction 201502_S_AT, 215346_AT,223862_AT, ADAMDEC1, CCL5, GPR183, GPR34, ITGB5, 203037_S_AT, 226218_AT,BIRC3 216598_S_AT, 226066_AT, 206254_AT, 206134_AT, 1555759_A_AT,205419_AT, 244434_AT, 201125_S_AT, 210538_S_AT GO:0006916~anti-0.000124449 5.889770261 0.004815965 215223_S_AT, 216841_S_AT, SOD2,SOD2, TNFAIP3, MALT1, IL10, NFKBIA, apoptosis 202644_S_AT, 210017_AT,SOD2, GHRL, CCL2, TNFSF13B, BIRC3 207433_AT, 201502_S_AT, 221477_S_AT,223862_AT, 216598_S_AT, 223502_S_AT, 210538_S_AT GO:0043066~negative0.000129722 4.527249623 0.004891125 215223_S_AT, 210017_AT, 201502_S_AT,SOD2, MALT1, NFKBIA, GHRL, CHST11, CCL2, regulation of apoptosis223862_AT, 219634_AT, MITF, TNFSF13B, SOD2, TNFAIP3, IL10, SOD2,216598_S_AT, 226066_AT, BIRC3 223502_S_AT, 216841_S_AT, 202644_S_AT,207433_AT, 221477_S_AT, 210538_S_AT GO:0060548~negative 0.0001473624.457599629 0.005158736 215223_S_AT, 210017_AT, 201502_S_AT, SOD2,MALT1, NFKBIA, GHRL, CHST11, CCL2, regulation of cell death 223862_AT,219634_AT, MITF, TNFSF13B, SOD2, TNFAIP3, IL10, SOD2, 216598_S_AT,226066_AT, BIRC3 223502_S_AT, 216841_S_AT, 202644_S_AT, 207433_AT,221477_S_AT, 210538_S_AT GO:0043069~negative 0.000142772 4.4748104390.005247712 215223_S_AT, 210017_AT, 201502_S_AT, SOD2, MALT1, NFKBIA,GHRL, CHST11, CCL2, regulation of programmed 223862_AT, 219634_AT, MITF,TNFSF13B, SOD2, TNFAIP3, IL10, SOD2, cell death 216598_S_AT, 226066_AT,BIRC3 223502_S_AT, 216841_S_AT, 202644_S_AT, 207433_AT, 221477_S_AT,210538_S_AT GO:0009893~positive 0.000147162 2.926706827 0.005277077213891_S_AT, 215223_S_AT, TCF4, SOD2, ADAM9, P2RX4, CD40, NFKBIA,regulation of metabolic 202381_AT, 204088_AT, SRA1, CD40, PRDM1, TCF4,MITF, TNFSF13B, process 205153_S_AT, 201502_S_AT, MAFB, EGF, PTX3,HNRPLL, SOD2, ICAM1, IL10, 224130_S_AT, 215346_AT, SOD2, NOD2, ICAM1228964_AT, 212387_AT, 226066_AT, 223502_S_AT, 218559_S_AT, 206254_AT,206157_AT, 225386_S_AT, 216841_S_AT, 202637_S_AT, 207433_AT,221477_S_AT, 220066_AT, 202638_S_AT GO:0031347~regulation of 0.0001659478.381024096 0.005672844 203980_AT, 207433_AT, FABP4, IL10, NFKBIA, CCL5,NOD2, GHRL, NT5E defense response 201502_S_AT, 1555759_A_AT, 220066_AT,223862_AT, 203939_AT GO:0006952~defense 0.000177009 3.9634399670.005912766 210017_AT, 201743_AT, 205153_S_AT, MALT1, CD14, CD40,TNFAIP6, CD40, CCL2, response 206026_S_AT, 215346_AT, PTX3, IFIH1, IL10,CCL5, NOD2, KYNU, CD55, 216598_S_AT, 206157_AT, KYNU, CD55 219209_AT,207433_AT, 1555759_A_AT, 220066_AT, 210663_S_AT, 201926_S_AT,217388_S_AT, 1555950_A_AT GO:0050708~regulation of 0.00018634716.99378158 0.00608588 202381_AT, 207433_AT, 205153_S_AT, ADAM9, IL10,CD40, CD40, NOD2, EGF protein secretion 215346_AT, 220066_AT, 206254_ATGO:0051704~multi- 0.000215223 3.337240364 0.006727739 210017_AT,201743_AT, 201502_S_AT, MALT1, CD14, NFKBIA, GHRL, IFNGR1, CCL2,organism process 223862_AT, 211676_S_AT, PTX3, THBD, ICAM1, IL10, IFIH1,CCL5, NOD2, 216598_S_AT, 206157_AT, MMP1, ICAM1 203887_S_AT,202637_S_AT, 207433_AT, 219209_AT, 1555759_A_AT, 220066_AT, 204475_AT,202638_S_AT GO:0032880~regulation of 0.00021195 8.016631744 0.006769334203927_AT, 202381_AT, 207433_AT, NFKBIE, ADAM9, IL10, CD40, NFKBIA,CD40, protein localization 205153_S_AT, 201502_S_AT, NOD2, EGF215346_AT, 220066_AT, 206254_AT GO:0002697~regulation of 0.00023371310.53614458 0.007006643 210017_AT, 202637_S_AT, 207433_AT, MALT1, ICAM1,IL10, CD40, CD40, NOD2, IL7R, immune effector process 205153_S_AT,215346_AT, ICAM1 220066_AT, 226218_AT, 202638_S_AT GO:0002706~regulationof 0.000238915 15.96385542 0.007019318 210017_AT, 207433_AT,205153_S_AT, MALT1, IL10, CD40, CD40, NOD2, IL7R lymphocyte mediated215346_AT, 220066_AT, 226218_AT immunity GO:0080134~regulation of0.000230106 5.387801205 0.007042074 213503_X_AT, 203980_AT, ANXA2P1,FABP4, ANXA2P2, IL10, ANXA2P1, response to stress 208816_X_AT,207433_AT, NFKBIA, ANXA2P1, CCL5, NOD2, GHRL, NT5E 210427_X_AT,201502_S_AT, 201590_X_AT, 1555759_A_AT, 220066_AT, 223862_AT, 203939_ATGO:0032502~developmental 0.000273185 1.891259305 0.007865563219358_S_AT, 213503_X_AT, ADAP2, ANXA2P1, MALT1, ANXA2P1, PLAUR, process210017_AT, 210427_X_AT, PRDM1, VPS33A, GHRL, IL7R, CCL2, MAFB,214866_AT, 228964_AT, 204590_X_AT, DAB2, TGM5, STATH, IL10, MMP9, SOD2,223862_AT, 226218_AT, GPR183, SOD2, CRYBB2, ADAM9, FABP4, 216598_S_AT,218559_S_AT, ANXA2P2, ANXA2P1, SRA1, CAST, CHST11, 201278_AT,207911_S_AT, MITF, EGF, MXD1, SOD2, THBD, MLF1, CCL5, 206835_AT,207433_AT, 203936_S_AT, CD9 221477_S_AT, 205419_AT, 215223_S_AT,206777_S_AT, 202381_AT, 203980_AT, 208816_X_AT, 201590_X_AT,224130_S_AT, 208908_S_AT, 219634_AT, 226066_AT, 206254_AT, 226275_AT,216841_S_AT, 203887_S_AT, 204784_S_AT, 1555759_A_AT, 201005_ATGO:0048584~positive 0.000283953 6.152493184 0.008017793 210017_AT,203980_AT, MALT1, FABP4, NFKBIA, CCL5, NOD2, GHRL, regulation ofresponse to 201502_S_AT, 1555759_A_AT, CD55,TNFSF13B, CD55 stimulus220066_AT, 223862_AT, 201926_S_AT, 223502_S_AT, 1555950_A_ATGO:0007155~cell adhesion 0.000307737 3.718639263 0.008523348209933_S_AT, 213428_S_AT, CD300A, COL6A1, ADAM9, CD36, TNFAIP6,202381_AT, 209555_S_AT, MTSS1, CCL2, LPXN, ICAM1, CCL5, ITGB5, CD9,206026_S_AT, 203037_S_AT, ICAM1 216598_S_AT, 216250_S_AT, 202637_S_AT,1555759_A_AT, 201125_S_AT, 201005_AT, 202638_S_AT GO:0022610~biologieal0.000315533 3.707734162 0.008578876 209933_S_AT, 213428_S_AT, CD300A,COL6A1, ADAM9, CD36, TNFAIP6, adhesion 202381_AT, 209555_S_AT, MTSS1,CCL2, LPXN, ICAM1, CCL5, ITGB5, CD9, 206026_S_AT, 203037_S_AT, ICAM1216598_S_AT, 216250_S_AT, 202637_S_AT, 1555759_A_AT, 201125_S_AT,201005_AT, 202638_S_AT GO:0002684~positive 0.000324184 6.0206540450.008651889 210017_AT, 202637_S_AT, MALT1, ICAM1, CD40, NFKBIA, CD40,NOD2, regulation of immune 205153_S_AT, 201502_S_AT, CD55, IL7R,TNFSF13B, ICAM1, CD55 system process 215346_AT, 220066_AT, 201926_S_AT,226218_AT, 223502_S_AT, 202638_S_AT, 1555950_A_AT GO:0001775~cellactivation 0.000386538 4.990805327 0.010124588 202381_AT, 210017_AT,202637_S_AT, ADAM9, MALT1, ICAM1, IL10, P2RX4, CD40, 207433_AT,204088_AT, CD40, GPR183, CD9, IL7R, ICAM1 205153_S_AT, 215346_AT,205419_AT, 201005_AT, 226218_AT, 202638_S_AT GO:0045429~positive0.000407508 26.34036145 0.010484798 215223_S_AT, 216841_S_AT, SOD2,SOD2, ICAM1, P2RX4, SOD2, ICAM1, regulation of nitric oxide 202637_S_AT,204088_AT, PTX3 biosynthetic process 221477_S_AT, 202638_S_AT, 206157_ATGO:0002703~regulation of 0.00041591 13.86334813 0.01051636 210017_AT,207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, NOD2, IL7R leukocytemediated 215346_AT, 220066_AT, 226218_AT immunity GO:0048856~anatomical0.000458417 2.018715984 0.011389929 219358_S_AT, 213503_X_AT, ADAP2,ANXA2P1, MALT1, ANXA2P1, PRDM1, structure development 210017_AT,210427_X_AT, PLAUR, VPS33A, GHRL, IL7R, CCL2, MAFB, DAB2, 228964_AT,214866_AT, 204590_X_AT, TGM5, STATH, IL10, MMP9, SOD2, GPR183,223862_AT, 226218_AT, SOD2, CRYBB2, ADAM9, ANXA2P2, ANXA2P1,216598_S_AT, 212559_S_AT, CAST, CHST11, MITF, EGF, SOD2, MLF1, CD9201278_AT, 207911_S_AT, 206835_AT, 207433_AT, 203936_S_AT, 221477_S_AT,205419_AT, 215223_S_AT, 206777_S_AT, 202381_AT, 208816_X_AT,201590_X_AT, 208908_S_AT, 219634_AT, 226066_AT, 206254_AT, 216841_S_AT,204784_S_AT, 201005_AT GO:0046903~secretion 0.000554725 5.5090952040.013539046 201278_AT, 206835_AT, DAB2, STATH, ANXA2P1, ANXA2P2,ANXA2P1, 213503_X_AT, 208816_X_AT, ANXA2P1, CCL5, VPS33A, GHRL, TNFSF13B210427_X_AT, 201590_X_AT, 1555759_A_AT, 204590_X_AT, 223862_AT,223502_S_AT GO:0050727~regulation of 0.000612986 12.54302926 0.01470747203980_AT, 207433_AT, 1555759_A_AT, FABP4, IL10, CCL5, GHRL, NT5Einflammatory response 223862_AT, 203939_AT GO:0048731~system 0.0006353942.065910702 0.014997197 219358_S_AT, 213503_X_AT, ADAP2, ANXA2P1, MALT1,ANXA2P1, PRDM1, development 210017_AT, 210427_X_AT, PLAUR, GHRL, VPS33A,IL7R, CCL2, MAFB, 228964_AT, 214866_AT, 223862_AT, STATH, TGM5, IL10,MMP9, SOD2, GPR183, 204590_X_AT, 226218_AT, SOD2, CRYBB2, ADAM9,ANXA2P2, ANXA2P1, 216598_S_AT, 218559_S_AT, CHST11, MITF, EGF, SOD2,MLF1, CD9 206835_AT, 207911_S_AT, 207433_AT, 203936_S_AT, 221477_S_AT,205419_AT, 215223_S_AT, 206777_S_AT, 202381_AT, 208816_X_AT,201590_X_AT, 219634_AT, 226066_AT, 206254_AT, 216841_S_AT, 204784_S_AT,201005_AT GO:0031226~intrinsic to 0.000511383 2.901401351 0.015933223202381_AT, 207536_S_AT, ADAM9, TNFRSF9, CD36, P2RX4, FXYD2, CD40, plasmamembrane 209555_S_AT, 204088_AT, CD40, IFNGR1, THBD, ICAM1, GPR183, CD9,207434_S_AT, 205153_S_AT, CD55, ITGB5, GPR34, CD55, STEAP1, ICAM1215346_AT, 211676_S_AT, 203887_S_AT, 202637_S_AT, 205419_AT, 201005_AT,201926_S_AT, 201125_S_AT, 244434_AT, 1555950_A_AT, 205542_AT,202638_S_AT GO:0051051~negative 0.00074669 8.209982788 0.017324877203927_AT, 200760_S_AT, 207433_AT, NFKBIE, ARL6IP5, IL10, NFKBIA, GHRL,ARL6IP5, regulation of transport 201502_S_AT, 223862_AT, EGF200761_S_AT, 206254_AT GO:0051050~positive 0.000772048 6.3036762430.017630829 202381_AT, 207433_AT, 204088_AT, ADAM9, IL10, P2RX4, NFKBIA,NOD2, GHRL, regulation of transport 201502_S_AT, 220066_AT, PTX3223862_AT, 206157_AT GO:0051384~response to 0.000868651 11.452331060.019513971 202381_AT, 203980_AT, 207433_AT, ADAM9, FABP4, IL10, CCL5,CCL2 glucocorticoid stimulus 1555759_A_AT, 216598_S_ATGO:0005625~soluble 0.000768008 4.517896389 0.019903205 215223_S_AT,213503_X_AT, SOD2, ANXA2P1, FABP4, ANXA2P1, ANXA2P1, fraction 203980_AT,210427_X_AT, TNFSF13B, EGF, SOD2, CCL5, SOD2, KYNU, 201590_X_AT,223502_S_AT, GPR34, CD55, KYNU, CD55 206254_AT, 216841_S_AT,1555759_A_AT, 221477_S_AT, 210663_S_AT, 244434_AT, 201926_S_AT,217388_S_AT, 1555950_A_AT GO:0031325~positive 0.000976424 2.7015755330.021581183 213891_S_AT, 215223_S_AT, TCF4, SOD2, ADAM9, P2RX4, CD40,NFKBIA, regulation of cellular 202381_AT, 204088_AT, SRA1, CD40, TCF4,MITF, MAFB, EGF, PTX3, metabolic process 205153_S_AT, 201502_S_AT,HNRPLL, SOD2, ICAM1, IL10, SOD2, NOD2, 224130_S_AT, 215346_AT, ICAM1212387_AT, 226066_AT, 218559_S_AT, 206254_AT, 206157_AT, 225386_S_AT,216841_S_AT, 202637_S_AT, 207433_AT, 221477_S_AT, 220066_AT, 202638_S_ATGO:0050817~coagulation 0.001021169 10.9751506 0.022226472 209555_S_AT,203887_S_AT, CD36, THBD, CD40, PLAUR, CD40, CD9 205153_S_AT, 214866_AT,215346_AT, 201005_AT GO:0007596~blood 0.001021169 10.9751506 0.022226472209555_S_AT, 203887_S_AT, CD36, THBD, CD40, PLAUR, CD40, CD9 coagulation205153_S_AT, 214866_AT, 215346_AT, 201005_AT GO:0031960~response to0.001104078 10.75116794 0.023661309 202381_AT, 203980_AT, 207433_AT,ADAM9, FABP4, IL10, CCL5, CCL2 corticosteroid stimulus 1555759_A_AT,216598_S_AT GO:0051047~positive 0.0001104078 10.75116794 0.023661309202381_AT, 207433_AT, 204088_AT, ADAM9, IL10, P2RX4, NOD2, GHRLregulation of secretion 220066_AT, 223862_AT GO:0030097~hemopoiesis0.001226255 4.816523236 0.025151654 215223_S_AT, 216841_S_AT, SOD2,SOD2, MALT1, IL10, MMP9, MLF1, SOD2, 210017_AT, 207433_AT, GPR183,VPS33A, IL7R 203936_S_AT, 204784_S_AT, 221477_S_AT, 205419_AT,204590_X_AT, 226218_AT GO:0007275~multicellular 0.001212038 1.8568923210.025215437 219358_S_AT, 213503_X_AT, ADAP2, ANXA2P1, MALT1, ANXA2P1,PLAUR, organismal development 210017_AT, 210427_X_AT, PRDM1, VPS33A,GHRL, IL7R, CCL2, MAFB, 214866_AT, 228964_AT, 204590_X_AT, DAB2, TGM5,STATH, IL10, MMP9, SOD2, 223862_AT, 226218_AT, GPR183, SOD2, CRYBB2,ADAM9, ANXA2P2, 216598_S_AT, 218559_S_AT, ANXA2P1, CHST11, MITF, EGF,MXD1, SOD2, 201278_AT, 207911_S_AT, THBD, MLF1, CD9 206835_AT,207433_AT, 203936_S_AT, 221477_S_AT, 205419_AT, 215223_S_AT,206777_S_AT, 202381_AT, 208816_X_AT, 201590_X_AT, 219634_AT, 226066_AT,206254_AT, 226275_AT, 216841_S_AT, 203887_S_AT, 204784_S_AT, 201005_ATGO:0010033~response to 0.001204931 2.951937059 0.025426793 202381_AT,201743_AT, 203980_AT, ADAM9, CD14, FABP4, MALT1, P2RX4, NFKBIA, organicsubstance 210017_AT, 204088_AT, GHRL, CCL2, THBD, IL10, CCL5, NOD2,KYNU, 201502_S_AT, 223862_AT, KYNU 216598_S_AT, 203887_S_AT, 207433_AT,1555759_A_AT, 220066_AT, 210663_S_AT, 217388_S_AT hsa04621: NOD-like0.000725707 7.947169811 0.026503364 202644_S_AT, 201502_S_AT, TNFAIP3,NFKBIA, CCL5, NOD2, CD2, BIRC3 receptor signaling pathway 1555759_A_AT,220066_AT, 216598_S_AT, 210538_S_AT GO:0002252~immune 0.001366377.18373434 0.027603619 202637_S_AT, 220066_AT, ICAM1, NOD2, CD55, IL7R,TNFSF13B, ICAM1, effector process 201926_S_AT, 226218_AT, CD55, PTX3223502_S_AT, 202638_S_AT, 1555950_A_AT, 206157_AT GO:0032680~regulationof 0.001395324 17.56024096 0.027800016 201743_AT, 207433_AT, CD14, IL10,NOD2, GHRL tumor necrosis factor 220066_AT, 223862_AT productionGO:0006954~inflammatory 0.001443579 4.682730924 0.028365247 201743_AT,207433_AT, 205153_S_AT, CD14, IL10, CD40, CD40, TNFAIP6, CCL5, CD55,response 215346_AT, 206026_S_AT, CCL2, CD55, PTX3 1555759_A_AT,201926_S_AT, 216598_S_AT, 1555950_A_AT, 206157_AT GO:0007599~hemostasis0.001483225 9.939759036 0.028750558 209555_S_AT, 203887_S_AT, CD36,THBD, CD40, PLAUR, CD40, CC9 205153_S_AT, 214866_AT, 215346_AT,201005_AT GO:0051173~positive 0.001639177 3.039272475 0.03014551213891_S_AT, 215223_S_AT, TCF4, SOD2, CD40, P2RX4, SRA1, CD40, NFKBIA,regulation of nitrogen 205153_S_AT, 204088_AT, TCF4, MITF, PTX3, MAFB,HNRPLL, SOD2, IL10, compound metabolic 224130_S_AT, 215346_AT,201502_S_AT, ICAM1, SOD2, ICAM1 process 212387_AT, 226066_AT, 206157_AT,218559_S_AT, 225386_S_AT, 216841_S_AT, 207433_AT, 202637_S_AT,221477_S_AT, 202638_S_AT GO:0051240~positive 0.001622601 5.4631860780.030221815 210017_AT, 201743_AT, MALT1, CD14, CD40, CD40, CCL5, NOD2,GHRL, regulation of multicellular 205153_S_AT, 215346_AT, CCL2organismal process 1555759_A_AT, 220066_AT, 223862_AT, 216598_S_ATGO:0042127~regulation of 0.00158235 2.859496441 0.0302467 215223_S_AT,207536_S_AT, SOD2, TNFRSF9, FABP4, CD40, CD40, NFKBIA, cellproliferation 203980_AT, 205153_S_AT, GHRL, CHST11, CCL2, MITF,TNFSF13B, EGF, 215346_AT, 201502_S_AT, 223862_AT, SOD2, IL10, SOD2, CD9219634_AT, 216598_S_AT, 226066_AT, 223502_S_AT, 206254_AT, 216841_S_AT,207433_AT, 221477_S_AT, 201005_AT GO:0005887~integral to 0.0013736732.758590942 0.030360284 207536_S_AT, 209555_S_AT, TNFRSF9, CD36, P2RX4,FXYD2, CD40, CD40, plasma membrane 204088_AT, 207434_S_AT, IFNGR1, THBD,ICAM1, GPR183, CD9, CD55, 205153_S_AT, 215346_AT, ITGB5, GPR34, CD55,STEAP1, ICAM1 211676_S_AT, 203887_S_AT, 202637_S_AT, 205419_AT,201005_AT, 201926_S_AT, 201125_S_AT, 244434_AT, 1555950_A_AT, 205542_AT,202638_S_AT GO:0050896~response to 0.0016107 1.733869102 0.030387009209933_S_AT, 209555_S_AT, CD300A, CD36, MALT1, P2RX4, CD40, NFKBIA,stimulus 210017_AT, 204088_AT, PLAUR, CD40, GHRL, IL7R, CCL2, IL10,NOD2, 205153_S_AT, 201502_S_AT, 214866_AT, SOD2, GPR183, CD55, KYNU,CD55, SOD2, 215346_AT, 223862_AT, CRYBB2, ADAM9, FABP4, CD14, TNFAIP6,226218_AT, 216598_S_AT, 207433_AT, IFNGR1, TNFSF13B, PTX3, SOD2, THBD,IFIH1, 220066_AT, 221477_S_AT, ICAM1, CCL5, KYNU, CD9, TREM1, ICAM1205419_AT, 201926_S_AT, 217388_S_AT, 1555950_A_AT, 215223_S_AT,206777_S_AT, 202381_AT, 203980_AT, 201743_AT, 206026_S_AT, 211676_S_AT,223502_S_AT, 206157_AT, 216841_S_AT, 203887_S_AT, 219209_AT,202637_S_AT, 1555759_A_AT, 210663_S_AT, 201005_AT, 219434_AT,202638_S_AT GO:0002700~regulation of 0.001768391 16.2094532 0.032085435210017_AT, 207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, NOD2production of molecular 215346_AT, 220066_AT mediator of immuneGO:0042113~B cell 0.001821278 9.407271945 0.032628793 210017_AT,207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, GPR183, IL7R activation215346_AT, 205419_AT, 226218_AT GO:0007165~signal 0.0019883491.864144476 0.034728937 209555_S_AT, 210017_AT, 228708_AT, CD36, MALT1,RAB27B, P2RX4, PLAUR, NFKBIA, transduction 204088_AT, 214866_AT, GHRL,IL7R, CCL2, IL10, FGL2, NOD2, GPR183, 201502_S_AT, 223862_AT, 226218_AT,ARHGAP18, LPAR6, ADAM9, ARHGAP18, 216598_S_AT, 207433_AT, TNFAIP6,MTSS1, IFNGR1, TNFSF13B, EGF, LPXN, 227265_AT, 220066_AT, 205419_AT,CCL5, GPR34, TREM1 225166_AT, 218589_AT, 202381_AT, 225171_AT,206026_S_AT, 203037_S_AT, 211676_S_AT, 223502_S_AT, 206254_AT,216250_S_AT, 1555759_A_AT, 244434_AT, 219434_AT GO:0048534~hemopoietic0.001967993 4.436271401 0.034791097 215223_S_AT, 216841_S_AT, SOD2,SOD2, MALT1, IL10, MMP9, MLF1, SOD2, or lymphoid organ 210017_AT,207433_AT, GPR183, VPS33A, IL7R development 203936_S_AT, 204784_S_AT,221477_S_AT, 205419_AT, 204590_X_AT, 226218_AT GO:0005102~receptor0.000373426 3.379393637 0.037380038 202381_AT, 204088_AT, 211725_S_AT,ADAM9, P2RX4, BID, MTSS1, GHRL, CCL2, binding 203037_S_AT, 223862_AT,TNFSF13B, EGF, BID, ADAMDEC1, ICAM1, IL10, 216598_S_AT, 223502_S_AT,FGL2, CCL5, BID, ICAM1 206254_AT, 227143_S_AT, 206134_AT, 202637_S_AT,207433_AT, 227265_AT, 1555759_A_AT, 204493_AT, 202638_S_ATGO:0050794~regulation of 0.002340559 1.349482027 0.040285453219358_S_AT, 213891_S_AT, ADAP2, TCF4, CD36, MALT1, P2RX4, NFE2L3,cellular process 209555_S_AT, 210017_AT, NFKBIA, DAB2, AGPAT9, MMP9,NOD2, SOD2, 204088_AT, 236471_AT, 201502_S_AT, BIRC3, ARHGAP18, SOD2,LPAR6, ADAM9, 201278_AT, 224480_S_AT, TNFRSF9, ARHGAP18, BID, NFE2L3,CHST11, 203936_S_AT, 220066_AT, MITF, PTX3, TNFSF13B, EGF, MXD1, SOD2,221477_S_AT, 210538_S_AT, TNFAIP3, CD9, BID, GLRX3, NFKBIE, RAB27B,225166_AT, 215223_S_AT, 218589_AT, CD40, PLAUR, PRDM1, CD40, GHRL, IL7R,TCF4, 202381_AT, 207536_S_AT, CCL2, MAFB, HNRPLL, BID, IL10, FGL2,GPR183, 225171_AT, 211725_S_AT, 204702_S_AT, FABP4, SRA1, TNFAIP6,MTSS1, IFNGR1, CYTIP, 219634_AT, 226066_AT, LPXN, ADAMDEC1, IFIH1,ICAM1, CCL5, GPR34, 206157_AT, 223502_S_AT, 206254_AT, TREM1, ICAM1226275_AT, 216841_S_AT, 202644_S_AT, 201005_AT, 204493_AT, 209080_X_AT,203927_AT, 228708_AT, 205153_S_AT, 214866_AT, 228964_AT, 215346_AT,223862_AT, 226218_AT, 212387_AT, 216598_S_AT, 218559_S_AT, 225386_S_AT,227143_S_AT, 207433_AT, 227265_AT, 205419_AT, 203980_AT, 224130_S_AT,206026_S_AT, 203037_S_AT, 211676_S_AT, 209606_AT, 216250_S_AT,206134_AT, 219209_AT, 202637_S_AT, 1555753_A_AT, 244434_AT, 219434_AT,202638_S_AT GO:0046651~lymphocyte 0.002435526 14.53261321 0.041404807210017_AT, 207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, IL7Rproliferation 215346_AT, 226218_AT GO:0070661~leukocyte 0.00268797814.04819277 0.045084782 210017_AT, 207433_AT, 205153_S_AT, MALT1, IL10,CD40, CD40, IL7R proliferation 215346_AT, 226218_ATGO:0032943~mononuclear 0.002687978 14.04819277 0.045084782 210017_AT,207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, IL7R cell proliferation215346_AT, 226218_AT GO:0002520~immune 0.002858408 4.1521752030.047340765 215223_S_AT, 216841_S_AT, SOD2, SOD2, MALT1, IL10, MMP9,MLF1, SOD2, system development 210017_AT, 207433_AT, GPR183, VPS33A,IL7R 203936_S_AT, 204784_S_AT, 221477_S_AT, 205419_AT, 204590_X_AT,226218_AT GO:0042994~cytoplasmic 0.002996182 35.12048193 0.049019173203927_AT, 207433_AT, 201502_S_AT NFKBIE, IL10, NFKBIA sequestering oftranscription factor GO:0042100~B cell 0.002996182 35.120481930.049019173 207433_AT, 205153_S_AT, IL10, CD40, CD40, IL7R proliferation215346_AT, 226218_AT Pathways significantly enriched among genesupregulated by Probioglat relative to GA (mannitol-corrected comparison)at 6 hours, earlier run including Kegg and GO BP only: Fold CategoryTerm Pathway Enrichment PValue Benjamini Probesets Genes KEGG_(—)hsa04060 Cytokine-cytokine receptor 4.35698707 1.27E−04 0.009767343204912_AT, 204533_AT, 207536_S_AT, IL10RA, CXCL10, TNFRSF9, IL10, CD40,CD40, PATHWAY interaction 207433_AT, 205153_S_AT, CCL5, IFNGR1, IL7R,CCL22, TNFSF13B, EGF 215346_AT, 1555759_A_AT, 211676_S_AT, 226218_AT,216598_S_AT, 223502_S_AT, 206254_AT KEGG_(—) hsa04621 NOD-like receptorsignaling 10.04279131 2.62E−04 0.010033132 202644_S_AT, 201502_S_AT,TNFAIP3, NFKBIA, CCL5, NOD2, CCL2, BIRC3 PATHWAY pathway 1555759_A_AT,220066_AT, 216598_S_AT, 210538_S_AT GO_BP GO:0002237 response tomolecule of 13.53138285 1.85E−06 0.002747953 203887_S_AT, 210017_AT,201743_AT, THBD, MALT1, CD14, IL10, NFKBIA, CCL5, NOD2, bacterial origin207433_AT, 201502_S_AT, CCL2 1555759_A_AT, 220066_AT, 216598_S_AT GO_BPGO:0006955 immune response 3.794670407 3.41E−06 0.002530005 209933_S_AT,210017_AT, 201743_AT, CD300A, MALT1, CD14, EBI3, IL7R, CCL2, 219424_AT,226218_AT, TNFSF13B, PTX3, CXCL10, IFIH1, ICAM1, IL10, 216598_S_AT,223502_S_AT, 206157_AT, CCL5, KYNU, NOD2, GPR183, CD55, KYNU, 204533_AT,219209_AT, TREM1, CD55, ICAM1 202637_S_AT, 207433_AT, 1555759_A_AT,210663_S_AT, 220066_AT, 205419_AT, 201926_S_AT, 217388_S_AT, 219434_AT,1555950_A_AT, 202638_S_AT GO_BP GO:0042981 regulation of apoptosis3.437543465 6.44E−06 0.003180733 215223_S_AT, 202381_AT, 207536_S_AT,SOD2, ADAM9, TNFRSF9, MALT1, P2RX4, BID, 210017_AT, 204088_AT, NFKBIA,GHRL, CHST11, CCL2, MITF, TNFSF13B, 211725_S_AT, 201502_S_AT, BID, BTG1,SOD2, TNFAIP3, IFIH1, IL10, MMP9, 223862_AT, 219634_AT, SOD2, NOD2, BID,BIRC3 216598_S_AT, 226066_AT, 223502_S_AT, 227143_S_AT, 240347_AT,216841_S_AT, 202644_S_AT, 219209_AT, 207433_AT, 203936_S_AT,221477_S_AT, 220066_AT, 204493_AT, 210538_S_AT GO_BP GO:0043067regulation of programmed 3.403676042 7.38E−06 0.002735716 215223_S_AT,202381_AT, 207536_S_AT, SOD2, ADAM9, TNFRSF9, MALT1, P2RX4, BID, celldeath 210017_AT, 204088_AT, NFKBIA, GHRL, CHST11, CCL2, MITF, TNFSF13B,211725_S_AT, 201502_S_AT, BID, BTG1, SOD2, TNFAIP3, IFIH1, IL10, MMP9,223862_AT, 219634_AT, SOD2, NOD2, BID, BIRC3 216598_S_AT, 226066_AT,223502_S_AT, 227143_S_AT, 240347_AT, 216841_S_AT, 202644_S_AT,219209_AT, 207433_AT, 203936_S_AT, 221477_S_AT, 220066_AT, 204493_AT,210538_S_AT GO_BP GO:0010941 regulation of cell death 3.3911471737.77E−06 0.00230315 215223_S_AT, 202381_AT, 207536_S_AT, SOD2, ADAM9,TNFRSF9, MALT1, P2RX4, BID, 210017_AT, 204088_AT, NFKBIA, GHRL, CHST11,CCL2, MITF, TNFSF13B, 211725_S_AT, 201502_S_AT, BID, BTG1, SOD2,TNFAIP3, IFIH1, IL10, MMP9, 223862_AT, 219634_AT, SOD2, NOD2, BID, BIRC3216598_S_AT, 226066_AT, 223502_S_AT, 227143_S_AT, 240347_AT,216841_S_AT, 202644_S_AT, 219209_AT, 207433_AT, 203936_S_AT,221477_S_AT, 220066_AT, 204493_AT, 210538_S_AT GO_BP GO:0009611 responseto wounding 4.116859404 1.28E−05 0.003159383 215223_S_AT, 209555_S_AT,SOD2, CD36, CD14, CD40, CD40, TNFAIP6, 201743_AT, 205153_S_AT, PLAUR,CCL2, PTX3, CXCL10, SOD2, THBD, IL10, 215346_AT, 206026_S_AT, 214866_AT,MGLL, CCL5, SOD2, CD9, CD55, CD55 216598_S_AT, 206157_AT, 204533_AT,216841_S_AT, 203887_S_AT, 207433_AT, 239914_AT, 1555759_A_AT,221477_S_AT, 201005_AT, 201926_S_AT, 1555950_A_AT GO_BP GO:0032496response to 13.22385142 1.35E−05 0.0028572 203887_S_AT, 201743_AT, THBD,CD14, IL10, NFKBIA, CCL5, NOD2, CCL2 lipopolysaccharide 207433_AT,201502_S_AT, 1555759_A_AT, 220066_AT, 216598_S_AT GO_BP GO:0045428regulation of nitric oxide 26.93747511 3.12E−05 0.005768335 215223_S_AT,216841_S_AT, SOD2, SOD2, ICAM1, IL10, P2RX4, SOD2, ICAM1, biosyntheticprocess 202637_S_AT, 207433_AT, PTX3 204088_AT, 221477_S_AT,202638_S_AT, 206157_AT GO_BP GO:0002684 positive regulation of 6.11186413.39E−05 0.005574201 210017_AT, 205153_S_AT, 215346_AT, MALT1, CD40,CD40, EBI3, NFKBIA, IL7R, immune system process 219424_AT, 201502_S_AT,TNFSF13B, CHRNB2, ICAM1, NOD2, CD55, CD55, 226218_AT, 223502_S_AT,241389_AT, ICAM1 202637_S_AT, 220066_AT, 201926_S_AT, 1555950_A_AT,202638_S_AT GO_BP GO:0002822 regulation of adaptive 15.8686217 3.47E−050.005133166 210017_AT, 207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40,NOD2, IL7R, immune response based on 215346_AT, 220066_AT, TNFSF13Bsomatic recombination of 226218_AT, 223502_S_AT immune receptors builtfrom immunoglobulin superfamily domains GO_BP GO:0002819 regulation ofadaptive 15.58525346 3.79E−05 0.005096778 210017_AT, 207433_AT,205153_S_AT, MALT1, IL10, CD40, CD40, NOD2, IL7R, immune response215346_AT, 220066_AT, TNFSF13B 226218_AT, 223502_S_AT GO_BP GO:0060341regulation of cellular 5.865417967 4.67E−05 0.005763766 203927_AT,202381_AT, 241389_AT, NFKBIE, ADAM9, CHRNB2, IL10, RAB27B, CD40,localization 207433_AT, 228708_AT, NFKBIA, CD40, NOD2, GHRL, EGF205153_S_AT, 201502_S_AT, 215346_AT, 220066_AT, 223862_AT, 206254_ATGO_BP GO:0050878 regulation of body fluid 8.253183863 4.82E−050.005486427 206835_AT, 213503_X_AT, STATH, ANXA2P1, CD36, THBD, ANXA2P2,levels 209555_S_AT, 203887_S_AT, ANXA2P1, CD40, PLAUR, ANXA2P1, CD40,CD9 208816_X_AT, 210427_X_AT, 205153_S_AT, 214866_AT, 201590_X_AT,215346_AT, 2011305_AT GO_BP GO:0006952 defense response 3.5478625756.58E−05 0.006947618 210017_AT, 201743_AT, 205153_S_AT, MALT1, CD14,CD40, CD40, TNFAIP6, CCL2, 215346_AT, 206026_S_AT, PTX3, CXCL10, TPSAB1,IFIH1, IL10, MGLL, CCL5, 216598_S_AT, 206157_AT, 204533_AT, NOD2, KYNU,CD55, KYNU, CD55 207741_X_AT, 219209_AT, 207433_AT, 239914_AT,1555759_A_AT, 220066_AT, 210663_S_AT, 201926_S_AT, 217388_S_AT,1555950_A_AT GO_BP GO:0051046 regulation of secretion 6.4803964876.85E−05 0.006751625 202381_AT, 241389_AT, 207433_AT, ADAM9, CHRNB2,IL10, RAB27B, P2RX4, CD40, 228708_AT, 204088_AT, CD40, NOD2, GHRL, EGF205153_S_AT, 215346_AT, 220066_AT, 223862_AT, 206254_AT GO_BP GO:0042127regulation of cell 3.142134962 7.26E−05 0.006714161 215223_S_AT,207536_S_AT, SOD2, TNFRSF9, FABP4, CD40, NFKBIA, EBI3, proliferation203980_AT, 205153_S_AT, CD40, GHRL, CHST11, CCL2, MITF, TNFSF13B,201502_S_AT, 219424_AT, 215346_AT, EGF, BTG1, CXCL10, SOD2, CHRNB2,IL10, SOD2, 223862_AT, 219634_AT, CD9 216598_S_AT, 226066_AT,223502_S_AT, 206254_AT, 240347_AT, 204533_AT, 216841_S_AT, 241389_AT,207433_AT, 221477_S_AT, 201005_AT GO_BP GO:0006916 anti-apoptosis6.355151895 7.86E−05 0.006835343 215223_S_AT, 216841_S_AT, SOD2, SOD2,TNFAIP3, MALT1, IL10, NFKBIA, 202644_S_AT, 210017_AT, SOD2, GHRL, CCL2,TNFSF13B, BIRC3 207433_AT, 201502_S_AT, 221477_S_AT, 223862_AT,216598_S_AT, 223502_S_AT, 210538_S_AT GO_BP GO:0051223 regulation ofprotein 8.931899642 1.24E−04 0.010183221 203927_AT, 202381_AT,207433_AT, NFKBIE, ADAM9, IL10, CD40, NFKBIA, CD40, transport205153_S_AT, 201502_S_AT, NOD2, EGF 215346_AT, 220066_AT, 206254_ATGO_BP GO:0043066 negative regulation of 4.52001701 1.42E−04 0.011048668215223_S_AT, 210017_AT, 201502_S_AT, SOD2, MALT1, NFKBIA, GHRL, CHST11,CCL2, apoptosis 223862_AT, 219634_AT, MITF, TNFSF13B, SOD2, TNFAIP3,IL10, SOD2, 216598_S_AT, 226066_AT, BIRC3 223502_S_AT, 216841_S_AT,202644_S_AT, 207433_AT, 221477_S_AT, 210538_S_AT GO_BP GO:0001775 cellactivation 5.068375108 1.43E−04 0.010557063 202381_AT, 210017_AT,241389_AT, ADAM9, MALT1, CHRNB2, ICAM1, IL10, P2RX4, 202637_S_AT,207433_AT, CD40, CD40, GPR183, CD9, IL7R, ICAM1 204088_AT, 205153_S_AT,215346_AT, 205419_AT, 201005_AT, 226218_AT, 202638_S_AT GO_BP GO:0043069negative regulation of 4.457064127 1.59E−04 0.011205923 215223_S_AT,210017_AT, 201502_S_AT, SOD2, MALT1, NFKBIA, GHRL, CHST11, CCL2,programmed cell death 223862_AT, 219634_AT, MITF, TNFSF13B, SOD2,TNFAIP3, IL10, SOD2, 216598_S_AT, 226066_AT, BIRC3 223502_S_AT,216841_S_AT, 202644_S_AT, 207433_AT, 221477_S_AT, 210538_S_AT GO_BPGO:0060548 negative regulation of cell 4.444683393 1.63E−04 0.010942714215223_S_AT, 210017_AT, 201502_S_AT, SOD2, MALT1, NFKBIA, GHRL, CHST11,CCL2, death 223862_AT, 219634_AT, MITF, TNFSF13B, SOD2, TNFAIP3, IL10,SOD2, 216598_S_AT, 226066_AT, BIRC3 223502_S_AT, 216841_S_AT,202644_S_AT, 207433_AT, 221477_S_AT, 210538_S_AT GO_BP GO:0042113 B cellactivation 11.48387097 1.65E−04 0.010566072 210017_AT, 241389_AT,207433_AT, MALT1, CHRNB2, IL10, CD40, CD40, GPR183, 205153_S_AT,215346_AT, IL7R 205419_AT, 226218_AT GO_BP GO:0070201 regulation ofestablishment 8.415178175 1.72E−04 0.01059381 203927_AT, 202381_AT,207433_AT, NFKBIE, ADAM9, IL10, CD40, NFKBIA, CD40, of proteinlocalization 205153_S_AT, 201502_S_AT, NOD2, EGF 215346_AT, 220066_AT,206254_AT GO_BP GO:0046903 secretion 4.84874552 1.99E−04 0.011766402201278_AT, 204533_AT, 206835_AT, DAB2, CXCL10, STATH, ANXA2P1, CHRNB2,213503_X_AT, 241389_AT, ANXA2P2, ANXA2P1, ANXA2P1, CCL5, VPS33A,208816_X_AT, 210427_X_AT, GHRL, TNFSF13B 201590_X_AT, 1555759_A_AT,204590_X_AT, 223862_AT, 223502_S_AT GO_BP GO:0009617 response tobacterium 6.029528107 3.40E−04 0.019214892 203887_S_AT, 210017_AT,201743_AT, THBD, MALT1, CD14, IL10, NFKBIA, CCL5, NOD2, 207433_AT,201502_S_AT, CCL2 1555759_A_AT, 220066_AT, 216598_S_AT GO_BP GO:0010033response to organic 3.026262807 3.46E−04 0.018159624 202381_AT,210017_AT, 201743_AT, ADAM9, MALT1, CD14, FABP4, P2RX4, NFKBIA,substance 203980_AT, 204088_AT, GHRL, HMGB2, CCL2, THBD, CHRNB2, IL10,201502_S_AT, 223862_AT, CCL5, NOD2, KYNU, KYNU 243368_AT, 216598_S_AT,203887_S_AT, 241389_AT, 207433_AT, 1555759_A_AT, 220066_AT, 210663_S_AT,217388_S_AT GO_BP GO:0032880 regulation of protein 7.378525791 3.51E−040.018439313 203927_AT, 202381_AT, 207433_AT, NFKBIE, ADAM9, IL10, CD40,NFKBIA, CD40, localization 205153_S_AT, 201502_S_AT, NOD2, EGF215346_AT, 220066_AT, 2006254_AT GO_BP GO:0006954 inflammatory response4.475765095 3.60E−04 0.018262369 204533_AT, 201743_AT, 207433_AT,CXCL10, CD14, IL10, MGLL, CD40, CD40, 239914_AT, 205153_S_AT, TNFAIP6,CCL5, CD55, CCL2, CD55, PTX3 215346_AT, 206026_S_AT, 1555759_A_AT,201926_S_AT, 216598_S_AT, 1555950_A_AT, 206157_AT GO_BP GO:0045429positive regulation of nitric 27.70711726 3.70E−04 0.018161517215223_S_AT, 216841_S_AT, SOD2, SOD2, ICAM1, P2RX4, SOD2, ICAM1, oxidebiosynthetic process 202637_S_AT, 204088_AT, PTX3 221477_S_AT,202638_S_AT, 206157_AT GO_BP GO:0002706 regulation of lymphocyte13.46873755 4.89E−04 0.023119461 210017_AT, 207433_AT, 205153_S_AT,MALT1, IL10, CD40, CD40, NOD2, IL7R mediated immunity 215346_AT,220066_AT, 226218_AT GO_BP G0:0051249 regulation of lymphocyte6.879976751 5.10E−04 0.023373393 210017_AT, 241389_AT, 207433_AT, MALT1,CHRNB2, IL10, CD40, EBI3, CD40, IL7R, activation 205153_S_AT, 219424_AT,TNFSF13B 215346_AT, 226218_AT, 223502_S_AT GO_BP GO:0051251 positiveregulation of 8.997672098 5.13E−04 0.022828997 210017_AT, 241389_AT,205153_S_AT, MALT1, CHRNB2, CD40, EBI3, CD40, IL7R, lymphocyteactivation 219424_AT, 215346_AT, TNFSF13B 226218_AT, 223502_S_AT GO_BPGO:0002697 regulation of immune 8.641328649 6.18E−04 0.026609275210017_AT, 202637_S_AT, 207433_AT, MALT1, ICAM1, IL10, CD40, CD40, NOD2,IL7R, effector process 205153_S_AT, 215346_AT, ICAM1 220066_AT,226218_AT, 202638_S_AT GO_BP GO:0050708 regulation of protein 12.53985916.42E−04 0.026859383 202381_AT, 207433_AT, 205153_S_AT, ADAM9, IL10,CD40, CD40, NOD2, EGF secretion 215346_AT, 220066_AT, 206254_AT GO_BPGO:0032101 regulation of response to 6.404003517 7.44E−04 0.030210271213503_X_AT, 203980_AT, ANXA2P1, FABP4, ANXA2P2, IL10, ANXA2P1, externalstimulus 208816_X_AT, 207433_AT, ANXA2P1, CCL5, GHRL, NTSE 210427_X_AT,201590_X_AT, 1555759_A_AT, 223862_AT, 203939_AT GO_BP GO:0002696positive regulation of 8.233718807 7.70E−04 0.030405582 210017_AT,241389_AT, 205153_S_AT, MALT1, CHRNB2, CD40, EBI3, CD40, IL7R, leukocyteactivation 219424_AT, 215346_AT, TNFSF13B 226218_AT, 223502_S_AT GO_BPGO:0002703 regulation of leukocyte 11.922314472 7.77E−04 0.029915725210017_AT, 207433_AT, 205153_S_AT, MALT1, IL10, CD40, CD40, NOD2, IL7Rmediated immunity 215346_AT, 220066_AT, 226218_AT GO_BP GO:0051050positive regulation of 5.218380828 8.05E−04 0.030169382 202381_AT,241389_AT, 207433_AT, ADAM9, CHRNB2, IL10, P2RX4, NFKBIA, NOD2,transport 204088_AT, 201502_S_AT, GHRL, PTX3 220066_AT, 223862_AT,206157_AT GO_BP GO:0007155 cell adhesion 2.909247312 8.70E−040.031759691 209933_S_AT, 213428_S_AT, CD300A, COL6A1, ADAM9, CD36,ATP2C1, 202381_AT, 209555_S_AT, TNFAIP6, MTSS1, ICAM2, CCL2, LPXN,ICAM1, 237278_X_AT, 206026_S_AT, CCL5, CD9, ITGB5, ICAM1 203037_S_AT,213620_S_AT, 216598_S_AT, 216250_S_AT, 202637_S_AT, 1555759_A_AT,201005_AT, 201125_S_AT, 202638_S_AT GO_BP GO:0051047 positive regulationof 8.007102693 8.73E−04 0.031121915 202381_AT, 241389_AT, 207433_AT,ADAM9, CHRNB2, IL10, P2RX4, NOD2, GHRL secretion 204088_AT, 220066_AT,223862_AT GO_BP GO:0051241 negative regulation of 6.208759507 8.74E−040.030436041 206835_AT, 213503_X_AT, 208816_X_AT, STATH, ANXA2P1,ANXA2P2, IL10, P2RX4, multicellular organismal 207433_AT, 204088_AT,ANXA2P1, ANXA2P1, NOD2, GHRL process 210427_X_AT, 201590_X_AT,220066_AT, 223862_AT GO_BP GO:0022610 biological adhesion 2.9050971738.81E−04 0.029962986 209933_S_AT, 213428_S_AT, CD300A, COL6A1, ADAM9,CD36, ATP2C1, 202381_AT, 209555_S_AT, TNFAIP6, MTSS1, ICAM2, CCL2, LPXN,ICAM1, 237278_X_AT, 206026_S_AT, CCL5, CD9, ITGB5, ICAM1 203037_S_AT,213620_S_AT, 216598_S_AT, 216250_S_AT, 202637_S_AT, 1555759_A_AT,201005_AT, 201125_S_AT, 202638_S_AT GO_BP GO:0030888 regulation of Bcell 20.78033794 8.82E−04 0.029309007 241389_AT, 207433_AT, 205153_S_AT,CHRNB2, IL10, CD40, CD40, TNFSF13B proliferation 215346_AT, 223502_S_ATGO_BP GO:0002694 regulation of leukocyte 6.133955176 9.31E−040.030258714 210017_AT, 241389_AT, 207433_AT, MALT1, CHRNB2, IL10, CD40,EBI3, CD40, IL7R, activation 205153_S_AT, 219424_AT, TNFSF13B 215346_AT,226218_AT, 223502_S_AT GO_BP GO:0050867 positive regulation of cell7.862830573 9.48E−04 0.030125327 210017_AT, 241389_AT, 205153_S_AT,MALT1, CHRNB2, CD40, EBI3, CD40, IL7R, activation 219424_AT, 215346_AT,TNFSF13B 226218_AT, 223502_S_AT GO_BP GO:0048584 positive regulation of4.930927647 0.001120224 0.034771388 210017_AT, 203980_AT, MALT1, FABP4,NFKBIA, CCL5, NOD2, GHRL, response to stimulus 201502_S_AT,1555759_A_AT, CD5S, TNFSF13B, CD55 220066_AT, 223862_AT, 201926_S_AT,223502_S_AT, 1555950_A_AT GO_BP GO:0030097 hemopoiesis 4.9309276470.001120224 0.034771388 215223_S_AT, 216841_S_AT, SOD2, SOD2, MALT1,IL10, MMP9, MLf1, SOD2, 210017_AT, 207433_AT, GPR183, VPS33A, IL7R203936_S_AT, 204784_S_AT, 221477_S_AT, 205419_AT, 204590_X_AT, 226218_ATGO_BP GO:0032680 regulation of tumor 18.7693375 0.00119195 0.03620158201743_AT, 207433_AT, CD14, IL10, NOD2, GHRL necrosis factor production220066_AT, 223862_AT GO_BP GO:0050865 regulation of cell activation5.818494624 0.001223425 0.036396133 210017_AT, 241389_AT, 207433_AT,MALT1, CHRNB2, IL10, CD40, EBI3, CD40, IL7R, 205153_S_AT, 219424_AT,TNFSF13B 215346_AT, 226218_AT, 223502_S_AT GO_BP GO:0045321 leukocyteactivation 4.808673243 0.00129524 0.037737147 202381_AT, 210017_AT,241389_AT, ADAM9, MALT1, CHRNB2, ICAM1, IL10, CD40, 202637_S_AT,207433_AT, CD40, GPR183, IL7R, ICAM1 205153_S_AT, 215346_AT, 205419_AT,226218_AT, 202638_S_AT GO_BP GO:0051173 positive regulation of 2.93635210.001352769 0.038623899 213891_S_AT, 215223_S_AT, TCF4, SOD2, CD40,P2RX4, SRA1, CD40, NFKBIA, nitrogen compound 205153_S_AT, 204088_AT,HMGB2, TCF4, MITF, MAFB, PTX3, HNRPLL, metabolic process 224130_S_AT,215346_AT, 201502_S_AT, SOD2, ICAM1, IL10, SOD2, ICAM1 243368_AT,212387_AT, 226066_AT, 218559_S_AT, 206157_AT, 225386_S_AT, 216841_S_AT,202637_S_AT, 207433_AT, 221477_S_AT, 202638_S_AT GO_BP GO:0051240positive regulation of 4.769257888 0.001358112 0.03804226 210017_AT,241389_AT, 201743_AT, MALT1, CHRNB2, CD14, CD40, CD40, CCL5,multicellular organismal 205153_S_AT, 215346_AT, NOD2, GHRL, CCL2process 1555759_A_AT, 220066_AT, 223862_AT, 216598_S_AT GO_BP GO:0001817regulation of cytokine 5.625616349 0.001454089 0.039925244 210017_AT,201743_AT, 207433_AT, MALT1, CD14, IL10, CD40, EBI3, CD40, NOD2,production 205153_S_AT, 219424_AT, GHRL 215346_AT, 220066_AT, 223862_ATGO_BP GO:0050727 regulation of inflammatory 9.569892473 0.0017688480.047488977 203980_AT, 207433_AT, 1555759_A_AT, FABP4, IL10, CCL5, GHRL,NT5E response 223862_AT, 203939_AT GO_BP GO:0010647 positive regulationof cell 3.979213648 0.001776941 0.046854541 210017_AT, 241389_AT,204088_AT, MALT1, CHRNB2, P2RX4, ATP2C1, CD40, CD40, communication237278_X_AT, 205153_S_AT, NOD2, GHRL, CCL2, EGF 215346_AT, 220066_AT,223862_AT, 216598_S_AT, 206254_AT GO_BP GO:0002250 adaptive immuneresponse 9.445608155 0.001856176 0.048042002 202637_S_AT, 207433_AT,219424_AT, ICAM1, IL10, EBI3, NOD2, CD55, ICAM1, CD55 220066_AT,201926_S_AT, 202638_S_AT, 1555950_A_AT GO_BP GO:0002460 adaptive immuneresponse 9.445608155 0.001856176 0.048042002 202637_S_AT, 207433_AT,219424_AT, ICAM1, IL10, EBI3, NOD2, CD55, ICAM1, CD55 based on somatic220066_AT, 201926_S_AT, recombination of immune 202638_S_AT,1555950_A_AT receptors built from immunoglobulin superfamily domainsGO_BP GO:0051384 response to glucocorticoid 9.324510615 0.001946450.043450316 202381_AT, 203980_AT, ADAM9, FABP4, IL10, CCL5, CCL2stimulus 207433_AT, 1555759_A_AT, 216598_S_AT GO_BP GO:0048534hemopoietic or lymphoid 4.475765095 0.001951531 0.048752558 215223_S_AT,216841_S_AT, SOD2, SOD2, MALT1, IL10, MMP9, MLF1, SOD2, organdevelopment 210017_AT, 207433_AT, GPR183, VPS33A, IL7R 203936_S_AT,204784_S_AT, 221477_S_AT, 205419_AT, 204590_X_AT, 226218_AT GO_BPGO:0048545 response to steroid 5.303315412 0.001961629 0.048188649202381_AT, 203980_AT, 207433_AT, ADAM9, FABP4, IL10, CCL5, GHRL, HMGB2,hormone stimulus 1555759_A_AT, 223862_AT, CCL2 243368_AT, 216598_S_ATGO_BP GO:0006959 humoral immune response 9.206478835 0.002039720.049246639 219424_AT, 205419_AT, 201926_S_AT, EBI3, GPR183, CD55,TREM1, CCL2, CD55 219434_AT, 216598_S_AT, 1555950_A_AT

Example 4 Validation of Pro-Inflammatory Markers' Upregulation byStimulation with Probioglat Compared to Copaxone® (gRT-PCR Analysis)

Key genes identified by differential expression analysis were assayedusing qRT-PCR. RNA was utilized from each of 6 biological samples foreach treatment (Copaxone and Probioglat) and 15 technical replicateswere performed for each sample (a total of 90 observations pertranscript per treatment). Since three Copaxone® batches and oneProbioglat batch were available, a total of 360 observations from eachtranscript were evaluated. To evaluate the data, the 2^(−ΔΔct)approximation was utilized with GAPDH as reference transcript andvehicle control (mannitol) as calibrator. A one-sided t-test withunequal variance was used to compare the RNA expression from the twotreatments.

To validate the results from the microarrays comparing Probioglat withCopaxone® for key inflammation and MS-related genes, two chemokines(CCL5, FDR p-value<0.02 and CXCL10, FDR p-value<0.0006), two matrixmetalloproteinases (MMP1, FDR p-value<0.002 and MMP9, FDRp-value<2.8e-6) and a non-secreted cell surface marker (CD9, FDRp-value<0.002 with FC 1.15) that is a component of myelin and a markerof myelinogenic progenitor cells (Allie et al., Arch. Neurol. 2005) weretested independently by robust qRT-PCR analysis. Three Copaxone® batchesand one Probioglat batch were available for use, and a total of 360observations from each transcript were evaluated. Statistical analysisutilized a one-sided t-test with unequal variance to compare the RNAexpression from the two treatments. All the genes tested weresignificantly differentially expressed between Probioglat and Copaxoneas expected based on the microarray analysis (Table 7).

TABLE 7 Differential expression (p value and fold change) of keyimmunological genes following Probioglat stimulation compared withCopaxone ® Genes CCL5 CD9 CXCL10 MMP1 MMP9 Method FC p value FC p valueFC p value FC p value FC p value qPCR 1.12 4.05E−05 1.11 0.0004 2.280.0029 1.25 0.0201 1.24 0.0168 FDR- 1.09 0.02 1.15 0.002 1.46 0.0006 1.50.002 1.29 2.80E−06 adjusted Microarray FC: fold change; qPCR;quantitative RT-PCR; FDR: For the microarray data, since all probesetson the microarray were tested, p values were adjusted using FDR fortesting multiple hypotheses.

Table 7 shows p-values from single-tailed t-test with unequal variance(for qPCR results) and FDR-adjusted p-values from LIMMA comparison ofmicroarray data between human monocytes treated with Copaxone® andProbioglat.

Discussion Examples 3-4

The genes significantly upregulated (FDR adjusted p value<0.05) inProbioglat relative to Copaxone® treatment at 6 hours were found to beenriched significantly (Benjamini corrected p value<0.05) for 106pathways annotated in the GO (Biological Process, Cellular Component,and Molecular Function) and Kegg databases (The Gene OntologyConsortium. Gene ontology: tool for the unification of biology, Nat.Genet., May 2000; Kanehisa et al, KEGG: Kyoto Encyclopedia of Genes andGenomes, N A R, 2000) (FIG. 10; Table 6). These include immune systemprocess (GO:0002376), response to lipopolysaccharide (LPS) (GO:0032496),and immune response (GO:0006955) pathways (Benjamini corrected p values1.5e-5, 8.7e-4, and 3.3e-4, respectively). Several of these pathways arerelevant to inflammation (e.g., regulation of inflammatory response(GO:0050727) and regulation of tumor necrosis factor production(GO:0032680), Benjamini corrected p values of 0.015 and 0.028,respectively).

Branded GA significantly modulated many validated pathways. At 6 hours,pathways enriched significantly among upregulated genes included broadcategories such as immune response and regulation of immune processes,and more specifically cytokine-cytokine receptor interactions. Othersignificantly enriched pathways included adhesion; extracellular region;plasma membrane; membrane; response to external stimulus; response tostress; response to wounding; defense response; inflammatory response;and immune system process, all pathways with broad relevance to thedisease process and/or proposed action of GA. Several of these pathways(e.g., extracellular region; immune system process; defense response;regulation of leukocyte activation) were also seen significantlyenriched among genes modulated by GA in monocytes obtained from RRMSpatients within the first two months of treatment (Thamilarasan, JNeuroinflammation 2013).

As another example, NOD-like receptor signaling (hsa04621, Benjaminicorrected p value 0.027) regulates inflammatory and apoptotic responses.The response to LPS pathway (GO:0050727; FIG. 9) includes the genesCD14, CCL5, THBD, CARD15, NFKBIA, and CCL2, all upregulated inProbioglat treatment versus GA at 6 hours. This pathway was alsosignificantly enriched among probesets upregulated by GA treatment at 6hours, though with a lower enrichment score (14.8 vs 2.7) and higher pvalue (0.00087 vs 0.036). The strong enrichment induced by Probioglatrelative to GA of this prototypical pro-inflammatory pathway warrantsfurther investigation with respect to safety.

Interestingly, about half of the pathways (58 out of 114) significantlyenriched (Benjamini corrected p value<0.05) among genes upregulated byGA treatment versus mannitol control at 6 hours were also significantlyenriched among genes upregulated by Probioglat relative to GA treatment.An additional 48 pathways were significantly enriched among genesupregulated by Probioglat relative to GA (and not modulated by GArelative to mannitol control). These include pathways relevant toinflammation, such as response to molecule of bacterial origin(GO:0002237), regulation of tumor necrosis factor production(GO:0032680) and NOD-like receptor signaling pathway (hsa04621), as wellas other immune pathways including regulation of lymphocyte mediatedimmunity (GO:0002706) and B cell proliferation (GO:0042100).

Example 5 Integrated Analysis Spanning Multiple Species and Cell Types

Analyses were conducted to elucidate the gene expression changes inducedby Copaxone® in the following systems:

-   -   1) primed, ex vivo mouse splenocytes;    -   2) THP-1 human monocyte cell line; and    -   3) samples from MS patients.

Genes, pathways and immune cell types modulated by Copaxone® wereinvestigated, in order to determine which aspects of Copaxone®'smechanism were observed across all systems utilized, and which weredetectable only in certain systems, but not others.

Genome-wide expression profiles in cells from three different datasetsin two different species (human, mouse) were studied. LIMMA was utilizedto identify a genome-wide list of differentially expressed genes inducedby GA in the primed and ex vivo stimulated mouse splenocytes, as well asin the THP-1 human monocyte cell line. Repeated-measures ANOVA wasutilized to find a genome-wide list of genes modulated by GA in treatedMS patients. Advanced enrichment algorithms were then applied toelucidate the pathways and cell types modulated by GA.

Upregulated expression of the IL-10 gene, a key indicator of thewell-studied Th2-shift induced by GA, was consistently demonstrated inall 3 systems (mouse splenocytes, human monocytes and MS patient PBMCs)(FIG. 13). GA induces an anti-inflammatory effect, mediated by secretionof IL-4, IL-10, and other anti-inflammatory cytokines. This effectinvolves both a shift in T cell populations (from pro-inflammatory Th1to anti-inflammatory Th2) and a shift from monocyte production of IL12to anti-inflammatory IL10. For example, in vitro GA treatment increasedthe proportion of IL10-producing Treg cells in blood from MS patients(Putheti, J Neuroimmunol 2003). Dendritic cells exposed to GA duringmaturation increased their production of IL10 (Vieira et al, J Immunol2003), monocytes from mice treated with GA secreted more IL10 thanmonocytes from untreated mice (Weber et al, Nat Med 2007), and monocytesisolated from MS patients treated with GA were shown to upregulate IL10relative to untreated patients (Kim et al, J Immunol 2004).

The genes modulated by GA treatment in multiple studies were examinedfor enrichment in particular immunological cell types. 39 genes weremodulated significantly by GA in all three studies (FIG. 14). Table 8shows the expression level of each gene as modulated by Copaxone®compared to baseline (human PBMC), mannitol (human monocyte) or medium(mouse splenocytes). Although some genes are significantlydifferentially expressed in the same direction across all compartmentsand systems, other genes are modulated differently across the differentsystems. This shows that Copaxone® may induce pathways or cell typesdifferently depending on a given experimental setup and a well-designedgenome-wide assay is required to ascertain mechanism and effect ofCopaxone®. Starred genes did not meet effect size cutoff of 0.5 employedin human PBMC study for conducting enrichments.

TABLE 8 Genes significantly modulated by Copaxone ® treatment in allthree studies Direction in Direction in Direction in human human mousePBMC monocytes splenocytes (Copaxone (Copaxone (Copaxone relative torelative to relative to Gene Baseline) Mannitol) Medium) ABCF2 DOWN DOWNUP ABI2 UP UP UP ACP6 DOWN DOWN DOWN AFG3L2 DOWN DOWN UP ALMS1 DOWN UPUP ARPC4 UP UP UP CALM3 UP DOWN DOWN CCDC64 UP DOWN DOWN CD84 UP UP DOWNCDC6 UP DOWN UP CHAF1A DOWN DOWN UP CLU UP UP DOWN COX11 DOWN DOWN UPDLGAP1 DOWN UP DOWN DTX4 DOWN UP DOWN FAM49B DOWN UP UP FHL1 UP DOWNDOWN FNTB UP DOWN DOWN GYPC UP DOWN DOWN HFE UP UP UP IL10* UP UP UPLPHN1 DOWN DOWN DOWN NACA* DOWN DOWN UP CLAH DOWN DOWN UP PATZ1 UP DOWNDOWN PDK1 UP DOWN DOWN POLI DOWN DOWN DOWN REEP5 DOWN UP DOWN RPL5* DOWNUP DOWN RPS6KA2 DOWN UP DOWN SEC31A DOWN DOWN DOWN SETBP1 DOWN UP DOWNSNRPA1 DOWN DOWN UP SYNCRIP DOWN DOWN DOWN TNF5F9 DOWN DOWN UP TOMM40DOWN DOWN UP TPM1 UP DOWN DOWN TSHZ1* DOWN DOWN DOWN TSP4N13 DOWN DOWNDOWN U6AP2 DOWN DOWN UP VAV3 DOWN UP DOWN VDAC2 DOWN DOWN UP ZFAND6 DOWNUP DOWN

Example 6 Cell Type Enrichment Analysis

In addition to the shared induced effects discussed above, each systemand platform clearly captured different aspects of GA's impact on theimmune system. In mouse splenocytes, genes associated with FOXP3+regulatory T cells (Tregs), B cells, T cells in general, macrophages,and dendritic cells were significantly modulated upon ex vivostimulation with GA after prior inoculation (Table 9). In human monocyte(THP-1) cells, upregulated genes were associated with monocytes alongwith NK cells, dendritic cells, and granulocytes (Table 10). In humanPBMCs, genes associated with immune cell types were modulated early intreatment (by month 3), including certain cell types affected in priorsystems, but also distinct cell types, such as megakaryocytes andmyeloid progenitors (Table 11).

TABLE 9 Immunological cell type enrichment for genes modulated by GAtreatment in mouse splenocytes Dataset Name¹ Score p.val adj.p.val a)Upregulated (top 20 results) SC.MEP.BM.rnk 641.2372079 0 0T.8Eff.Sp.OT1.12hr. 683.0376678 0 0 LisOva.rnk T.8Eff.Sp.OT1.48hr.587.7303361 0 0 LisOva.rnk T.DPbl.Th.rnk 659.3284877 0 0 T.ISP.Th.rnk584.8660167 0 0 preB.FrC.BM.rnk 620.1611981 0 0 proB.FrBC.FL.rnk595.3446445 0 0 DC.LC.Sk.rnk 709.8843317 2.89E−15 6.96E−14NK.H..MCMV1.Sp.rnk 770.77198 7.11E−15 1.52E−13 DC.103.11b..PolyIC.Lu.rnk704.9643794 1.44E−14 2.65E−13 NK.MCMV1.Sp.rnk 793.3059033 1.51E−142.65E−13 T.8Eff.Sp.OT1.24hr. 661.8125467 5.97E−14 9.61E−13 LisOva.rnkB.GC.Sp.rnk 602.4630175 1.01E−12 1.39E−11 Tgd.vg2.24ahi.e17.Th.rnk619.9621246 9.88E−13 1.39E−11 DC.103.11b.24..Lu.rnk 738.2608372 8.91E−121.15E−10 T.4FP3.25..AA.rnk 697.5960229 2.76E−11 3.14E−10Tgd.vg3.24alo.e17.Th.rnk 620.789896 2.72E−11 3.14E−10 proB.FrA.FL.rnk578.5853958 7.17E−11 7.69E−10 preT.DN3B.Th.rnk 567.9618687 1.64E−101.67E−09 preT.DN3.4.Th.rnk 560.7279837 2.96E−10 2.86E−09 b)Downregulated (top 20 results) GN.Arth.BM.rnk 1217.738372 0 0SC.CDP.BM.rnk 1077.505969 0 0 T.4SP24int.Th.rnk 1040.246786 0 0T.8Nve.Sp.OT1.rnk 1095.134864 0 0 proB.CLP.FL.rnk 1115.01089 0 0GN.BM.rnk 1212.480897 1.11E−16 3.57E−15 GN.BI.rnk 1184.87043 6.66E−151.84E−13 GN.UrAc.PC.rnk 1145.080376 5.87E−14 1.37E−12 GN.Thio.PC.rnk1197.163456 6.39E−14 1.37E−12 GN.Arth.SynF.rnk 1160.159783 2.72E−115.25E−10 DC.Ilhilang.103.11blo. 1112.24759 5.07E−08 8.90E−07 SLN.rnkDC.Ilhilang.103.11b..SLN.rnk 1151.229363 9.94E−08 1.60E−06DC.8.4.11b..SLN.rnk 1116.686609 1.86E−07 2.77E−06 proB.CLP.BM.rnk1181.133013 1.35E−06 1.86E−05 Mo.6C.Il..BM.rnk 1094.697148 1.71E−062.20E−05 DC.103.11b..LuLN.rnk 1151.971571 2.47E−06 2.98E−05SC.GMP.BM.rnk 1340.719659 1.56E−05 0.000164843 SC.MDP.BM.rnk 1206.2243591.56E−05 0.000164843 Mo.6C.Ilint.BI.rnk 1106.765118 1.62E−05 0.000164843¹All immunological cell type terminology in Tables 5-7 as defined viaImmgen (www.immgen.org/).

TABLE 10 Immunological cell type enrichment for genes upregulated by GAtreatment in human monocytes. Dataset Name Score p.val adj.p.valMONO2.rnk 108.0701335 0 0 NKA1.rnk 97.70225302 2.00E−15 3.80E−14MONO1.rnk 104.5121531 8.28E−13 1.05E−11 GRAN2.rnk 97.10283117 1.17E−091.11E−08 GRAN3.rnk 91.49890345 1.27E−07 9.40E−07 DENDA2.rnk 100.41778381.48E−07 9.40E−07 DENDA1.rnk 111.2455747 7.78E−05 0.000422143 EOS2.rnk94.29494842 0.000223937 0.001063701 MEGA2.rnk 101.6956549 0.0074425660.031424168

TABLE 11 Immunological cell type enrichment for genes modulated by GAtreatment in human PBMC. Dataset Name Score p.val adj.p.val Genes inlist >= threshold a) Upregulated, by cluster resulting from consensusk-means clustering on gene expression profiles Cluster 0: MEGA2.rnk32.42631137 1.24E−12 4.70E−11 PTPN18, ILK, RAB27B, FHL1, EPOR, FYN, MAX,PARVB, TUBB1, TPM1, VCL, TPM4 Cluster 2: PRE_BCELL3.rnk 57.938962973.98E−08 1.51E−06 IGL@, TOP2A, NUSAP1, IRF4, IGHM, IGL@, BIRC5 ERY5.rnk64.22953395 9.88E−07 1.88E−05 IGL@, TOP2A, NUSAP1, IGHM, MYL4, MKI67,IGL@, H2AFX, RPIP8, GYPC, BIRC5 ERY2.rnk 32.83132369 8.43E−050.001067894 BUB1B, TOP2A, NUSAP1, MCM4, TUBB, MYL4, CDC6, BIRC5 ERY4.rnk69.43612767 0.000141687 0.001346024 TOP2A, NUSAP1, TUBB, MYL4, MKI67,CDC2, RPIP8, GYPC, BIRC5 ERY3.rnk 84.61769579 0.000286865 0.002180171BUB1B, TOP2A, NUSAP1, TUBB, MYL4, MKI67, CDC2, RPIP8, GYPC, BIRC5GRAN1.rnk 55.17000868 0.000557705 0.003532132 IGHG1, IGL@, TOP2A,NUSAP1, IRF4, IGHM, IGL@, BIRC5 EOS2.rnk 62.69263216 0.0022862840.012411257 IGL@, IRF4, IGHM, IGL@ BASO1.rnk 87.29704767 0.0032197140.013594346 IGL@, IGHM, IGL@ ERY1.rnk 28.25494881 0.0030432240.013594346 BUB1B, NUSAP1, MCM4, TUBB, MS4A2, BIRC5 MEP.rnk 30.54460450.009387769 0.035673524 TOP2A, NUSAP1, MCM4, TUBB, MS4A2, BIRC5 Cluster4: MEGA2.rnk 64.4584783 4.41E−12 1.67E−10 PARD3, GNB5, C5ORF4, LIMS1,ACTN1, ITGB3, ITGA2B, GPX1, IGF2BP3, CLU, LTBP1 MEGA1.rnk 38.048179494.66E−09 8.86E−08 HMGA2, LIMS1, ACTN1, ITGB3, ITGA2B, GPX1, IGF2BP3,LTBP1 ERY2.rnk 47.24788403 4.70E−06 5.96E−05 HMGA2, LIMS1, ACTN1, ITGB3,ITGA2B, IGF2BP3, CLU, LTBP1 GMP.rnk 33.12681006 0.000142682 0.001355477ACTN1, GPX1, IGF2BP3, LTBP1 HSC3.rnk 45.40525942 0.000287455 0.002184658HMGA2, LIMS1, GPX1, IGF2BP3, HIST1H3D, LTBP1, INPP4B ERY5.rnk73.41821315 0.000980846 0.006212027 CLCN3, C5ORF4, ITGB3, GPX1, IGF2BP3,LTBP1 CMP.rnk 23.1944575 0.002214239 0.010517637 HMGA2, IGF2BP3 ERY4.rnk77.37714483 0.001966408 0.010517637 RAB6B, CLCN3, C5ORF4, GPX1, IGF2BP3,LTBP1 ERY1.rnk 45.00063371 0.002587112 0.010923363 HMGA2, GPX1, IGF2BP3,MALL, LTBP1 ERY3.rnk 90.0166825 0.009061135 0.031302103 RAB6B, CLCN3,C5ORF4, GPX1, IGF2BP3, LTBP1 GRAN2.rnk 35.17942767 0.0087500110.031302103 ACTN1, ITGB3, GPX1, IGF2BP3, LTBP1 b) Downregulated, bycluster resulting from consensus k-means clustering on gene expressionprofiles (as described in methods) Cluster 0: BCELLA2.rnk −25.766796460.000420072 0.015962749 ITSN1, ZNF365, GYG2 BCELLA1.rnk −19.111706980.002736809 0.025999686 ITSN1, ANK3, ZNF365, GYG2, EXTL2 BCELLA3.rnk−20.11301566 0.00138472 0.025999686 ITSN1, ZNF365, GYG2 BCELLA4.rnk−21.51318153 0.00253799 0.025999686 ITSN1, LILRA4, GYG2, EXTL2

Discussion Examples 5-6

The diversity of the cell types enriched from the list of 1200 genes (Bcells, T cells, monocyte progenitors, megakaryocytes) indicates thewide-ranging effects of Copaxone® on the immune system. Similar to whatwas observed in the splenocyte data, it is difficult to define a smallpanel of genes to use as quality-control measures against a givenCopaxone® lot due to the wide-ranging effect of the drug. Usinggenome-wide gene-expression arrays, the gene expression from the humanPBMC data, mouse splenocytes and human THP-1 monocyte cell line werecompared and discovered that although there are genes that areconsistently modulated by Copaxone® across all those experimentalsystems (e.g., IL10), some gene-expression signatures and cell types(e.g., B-cells) were seen only in one system (e.g., human PBMC data) butnot as clearly in the other systems (e.g., monocytes and splenocytedata). Looking at genome-wide gene expression signatures can yield agood characterization of the impact of Copaxone® on a single system(e.g., THP-1 monocytes) but well-powered experiments in multiple systemsare necessary to characterize the biological impact of Copaxone®.

The generic glatiramer acetate manufactured by Probioglat inducedsignificantly higher expression of CD14 than Copaxone® did (adj.p=0.0135; FIG. 15a ) and also induced significantly higher expression ofCD40 than Copaxone® did (adj. p=0.0128, FIG. 15b ). One key element ofCopaxone®'s putative mechanism of action is the ability to shift theimmune response from a Th1/Th17 phenotype, typically associated with MSpathoetiology and severity, to a Th2 response type that may mitigate theharmful effects of MS. Across multiple studies, we observed concerningdifferences between Copaxone® and proposed generics was observed intheir impact on key genes associated with maintaining the balancebetween Th2 and Th1/Th17.

Interleukin-1 beta (IL1B) is a cytokine that stimulates a variety ofimmune system cells, and may contribute to the development of MS bypromoting Th17 cell development. Consistent with these observations,IL1B has also been found to be associated with late disabilityprogression and neurodegeneration in MS. Glatiramer acetate, on theother hand, was reported to significantly reduce interleukin-1betalevels under chronic inflammatory conditions in vitro in human monocytes(p=0.028).

A variety of glatiramoids were significantly less effective thanCopaxone® at downregulating IL1B: Copaxone® induced significantly lowerIL1B expression than a Natco purported generic in our first mousesplenocyte study (adjusted p=0.043 by ANOVA). Copaxone® was alsoextremely effective in downregulating IL1B relative to medium (adjustedp=5.72×10-7), while the Hangzhou purported generic (API, China) did notsignificantly downregulate IL1B relative to medium (adjusted p=0.159)(FIG. 16).

Other Th17-associated genes also seem to be modulated less effectivelyby purported generics than by Copaxone®. In human monocytes, CD44 wasupregulated to a greater extent by Escadra635 than by Copaxone® (adj.p=0.04 by LIMMA at 6 hrs; FIG. 17). CD44 has an established role in Th17differentiation, specifically: “deletion of CD44 inhibited Th1/Th17differentiation while simultaneously enhancing Th2/regulatory T celldifferentiation.

Th17 associated genes also vary from one batch of generics to another.In mouse splenocytes, IL27 was upregulated to significantly differentextents by different batches of Escadra, namely Escadra635 andEscadra253 (FIG. 18). IL27 has been proposed to have therapeutic effectsin MS, due to its ability to suppress Th17 cells and stimulateneuroprotective factors.

In human monocytes, Probioglat induces significantly higher expressionof MMP9 than Copaxone does (Adj. p=2.07×10-5 by LIMMA for Copaxone vs.Probioglat at 6 hrs in human monocytes; FIG. 19). MMP9 is an establishedbiomarker and potential predictor of disease activity in MS. Thisfinding is particularly concerning given the fact that MMP9 facilitatesT-cell migration into the CNS, playing a key role in the disruption ofthe blood-brain barrier (BBB) and thus in the pathogenesis of MS.

Example 7 Compositional Differences of GARDPs and GARDSs

Due to its molecular diversity, characterizing even a single, largepolypeptide (assuming it could be isolated) would present significanttechnological and ° scientific barriers making full characterization, aswell as a demonstration of active ingredient sameness, impossible.

Analysis of Additional Purported Generics Reveals Limitations of FocusedGene Panels

Certain methods have been publicly described in patent applicationfilings by manufacturers seeking to develop purported generics(including International Publication Number WO2008/157697 by MomentaPharmaceuticals, Inc.), suggesting that glatiramoids can be compared byanalyzing a panel comprising only a small subset of proteins and/or thegenes coding for those proteins. To evaluate the effectiveness of suchcomparisons, we applied the same methods used to study Probioglat andCopaxone in human monocytes to also study purported generics Escadra(Raffo, Argentina) and Glatimer (Natco, India). Both purported genericsmodulated many genes to a significantly different extent than Copaxone.These differentially expressed genes included genes with relevance formultiple sclerosis. For instance, both Natco and Escadra differedsignificantly from Copaxone in expression of CD9, a component of myelinand a marker of myelinogenic progenitor cells (Sim et al, NatureBiotechnology, 2011). As another example, Escadra differed significantlyfrom Copaxone in expression of CD44, the receptor for hyaluronan whichaccumulates in demyelinated lesions (Back et al, Nature Medicine, 2005).Despite significant differences such as these between Copaxone and thepurported generics in expression of biologically relevant genes, when weexamined only the small subset of genes coding for proteins identifiedin the Momenta patent, there were no significant differences inexpression (FIG. 20). This demonstrates that methods focusing on only asmall selected subset of genes may miss important differences betweentwo glatiramoids.

Compositional Differences can be Observed Between Copaxone and OtherGenerics

TV-5010 was developed by making slight changes to the manufacturingprocess for Copaxone®, in order to produce a higher average molecularmass (in the range of 13,500-18,500 Daltons) and investigate whethersuch a change in molecular mass would be clinically beneficial.Surprisingly, TV-5010 proved toxic in long-term animal studies, inducingfibrosis, nephropathy, increases in eosinophil counts, and severeinjection site lesions, including subcutaneous necrosis, vascularnecrosis, cavity formation, and inflammation; in some cases theselesions were associated with mortality in both rats and monkeys,possibly related to vascular damage, hemorrhage, thrombus formation, andsepticemia. These toxicities were never seen in any of the developmentprograms for Copaxone, and led to the termination of TV-5010'sdevelopment. Some patients treated with TV-5010 showed injection sitereactions and/or developed anti-drug antibodies, but the clinicalstudies were completed in time to prevent any of the chronic toxicitiesobserved in long-term animal studies from potentially occurring inhumans. Because Copaxone® and TV-5010 had many similarities, with thetwo key differences that (1) TV-5010 had a higher average molecular massthan Copaxone®, and (2) Copaxone® was safe while TV-5010 inducedtoxicity in long-term animal studies, we sought to determine if therewere genes differentially expressed in response to the two medicinesthat could have predicted toxicity prior to the initiation of long-termanimal studies. Having generated gene expression profiles forTV-5010-stimulated splenocytes using the same procedures describedabove, we applied LIMMA to create a ranked list of genes withsignificantly different expression levels in response to TV-5010compared to Copaxone, with both analyzed relative to medium. Among thegenes with fold changes greater than 1.5, the gene with the lowest(best) p-value was Matrix Metalloproteinase 14 (MMP14). MMP14 expressionwas significantly higher in response to TV-5010 than in response toCopaxone® as determined by both ANOVA (adj p<4.53×10-7) and LIMMA (adjP<1.07×10-5) (FIG. 21).

The observed upregulation of MMP14 was striking because MMP14 has beenassociated with fibrosis and eosinophil-related disorders in theliterature, the very same toxicities seen in animals following long-termtreatment with TV-5010. MMP14 levels increase to over 250% of controlcorrelating with the pattern of fibrosis manifestation in rats, andMMP14 activity is chronically elevated in a mouse model of dermalfibrosis. Moreover, in patients with the eosinophil-related disorderEosinophilic Esophagitis (EoE), MMP14 is expressed at a 5.3-fold higherlevel than in controls. In addition to MMP14, another gene, SignalTransducer and Activator of Transcription 3 (STAT3), which has also beenlinked to fibrosis, also showed significantly elevated expression inresponse to TV-5010 relative to Copaxone®. Overall, our findings withTV-5010 lend further support to the utility of mouse splenocyte geneexpression studies for predicting drug safety issues.

Example 8 Clinical Implications of the Use of Purported Generics

Purported “generics” are not only different from Copaxone® in many ways,but also different from each other, causing differential effects in avariety of pathways modulating immunological processes that could haveclinical and biological significance. The differences among “generics”highlight the importance of the manufacturing process for glatirameracetate, and demonstrate that even slight changes in the manufacturingprocess can alter the biological properties of the resulting medicine(FIG. 22).

As part of Teva's ongoing commitment to better understand Copaxone®,Teva also has studied Copaxone®'s effect at the level of gene expressionacross the entire genome (unbiased, without prior hypothesis about thegenes for which expression pattern may be altered and without choosingwhich genes to focus on or study). Genes encode proteins which carry outan array of biological processes in the body, including processes thatare essential to the immune system response manifested by exposure toCopaxone®. So-called gene “microarray technology” allows scientists toobserve which genes are “turned on” (in scientific terms,“upregulated”), as well as which genes are “turned off” (in scientificterms, “downregulated”) after exposure to various conditions, includingstimulation by pharmaceutical products, via measuring the level of mRNA,which is the transitional phase between genes and proteins along thetranslation process. Teva's gene expression analysis of mousesplenocytes, as well as a human monocyte cell line (THP-1), exposed toCopaxone®, reveals favorable, upregulation of anti-inflammatory genes.These studies provide support for the vast experimental evidence thatCopaxone® exerts its well-established therapeutic benefits in part bymodulating the immune system to turn on beneficial (i.e.anti-inflammatory and neuro-protective) genes and turn off harmful ones(i.e. pro-inflammatory).

Several competitors have sought approval to market putative genericversions of the drug in foreign countries. Although many of thosejurisdictions have required applicants to conduct clinical trials as acondition of approval—and none of those jurisdictions has approved ageneric version of Copaxone®—others have not been as careful, and thosecountries since have allowed purported Copaxone generics to enter themarket without proof of the equivalence of the putative generics toCopaxone®.

In particular, the findings for Probioglat discussed below should becarefully addressed, given the serious clinical reports from Mexicofollowing introduction of this purported generic to the market. Thecomplaints expressed by MS patients treated with Probioglat in Mexicoincluded adverse reactions (increased injection site reactions and postinjection reactions) and increased occurrence of relapses, even inpatients who had been stable for years under Copaxone treatment. Theseeffects may be underlined by a biological imbalance betweenanti-inflammatory and pro-inflammatory processes, which may bediscernible in gene expression differences such as those describedherein. The pro-inflammatory signal identified in pre-clinical analysesand its potential association with boosting of the autoimmune mechanismsof disease following switching to Probioglat treatment should raiseconcerns for the potential health consequences of these differences.

The Teva Patient Support Program in Mexico has an extensive database.Given that patients can switch between branded and purported generic GA,all patients are kept within the database and are provided with patientsupport services. Interestingly, the database shows differences inpatient reports between 2012, when patients in the program werereceiving only Copaxone, vs 2013, when patients were receiving bothCopaxone® and Probioglat.

The number of relapses reported by patients in Teva's Patient SupportProgram on a monthly basis during the years 2012 and 2013 i. It is againclear that when Copaxone alone was in use (i.e. throughout 2012) theoverall, as well as per-month number of relapses was lower than thatreported when Probioglat was present in the market (i.e. throughout2013).

Discussion Examples 7-8

Gene expression data presented herein for Copaxone® further demonstratesthe highly complex mechanism of action of GA, given that many of theGA-induced functional pathways in these experiments coincide with knownmechanisms of GA activity in MS patients. Furthermore, the data suggeststhat other glatiramoids are associated with a significantly altered geneexpression profile and thus would probably not behave the same asCopaxone. Most importantly, these biological differences could lead to amarked difference in safety or efficacy profile over the course ofchronic treatment.

Probioglat, a purported generic of Copaxone®, has been in commercial usein Mexico since January 2013. The introduction of Probioglat hasresulted in a spike of injection site reactions and post injectionreactions, as well as occurrence of relapses, even in patients who hadbeen stably in remission for years. Accordingly, severalpharmacovigilance reports have been issued by HCPs, and patientsexpressed complaints in the local media and in Teva's Patient SupportProgram.

The high occurrence of relapses and adverse events after the treatmentswitch to Probioglat may be due to an immunological imbalance favoringpro-inflammatory effects, instead of the well recorded beneficial effectthat Copaxone induces, reducing pro-inflammation and boostinganti-inflammation.

Overall, similarities in the physicochemical properties of theglatiramer acetate mixture are observed between Copaxone and Probioglat,as well as other purported generics, particularly when using commonnon-specific analytical methods. However, clear differences are observedbetween Copaxone and purported generics when applying high resolutionmethodologies targeted at characterizing functionally relevant elements,e.g. IMMS analyses concomitantly capturing composition, size and chargedistribution; and gene expression analyses capturing pro-inflammationdistinctly upregulated by purported generics but not Copaxone®.

Gene expression studies thus help explain the biological impact of thephysicochemical differences observed, providing insight into some of thefactors that may underlie the observed reduction in efficacy andparallel increase in adverse events reported with purported genericglatiramer acetate, notably Probioglat in Mexico.

As part of Teva's ongoing commitment to better understand Copaxone®,Teva studies its effect at the level of gene expression across theentire genome (unbiased, without prior hypothesis about the genes forwhich expression pattern may be altered and without choosing which genesto focus on or study) in a variety of immunologically relevant modelsystems, including mouse splenocytes, human monocytes, and peripheralblood mononucleated cells (PBMCs) from MS patients. The genome-wideapproach is critical, because two glatiramoids can appear identicalbased on a small panel of genes, yet differ significantly in theirimpact on other genes that are potentially highly relevant to safetyand/or efficacy. Using multiple model systems is equally critical, sinceacting as an antigen, Copaxone significantly impacts a variety ofimmunological cell types. The unbiased approach allows identification ofgenes and pathways with subtle, yet robust, differential expressionpatterns following stimulation by different glatiramoids in differentexperimental contexts. The functionality of identified genes andpathways is then described based on experimental data reported in thepeer-reviewed literature. The research has also shown that various modelsystems capture different aspects of Copaxone's mechanism of action,such that no single cell type or system tested was sufficient to fullycharacterize the biological impact of this medicine.

Example 9 Differences in Gene Expression Induced by Polimunol VersusBranded GA

To identify differences between Copaxone® and differently manufacturedglatiramoids, differential gene expression analysis was performed inthis study to compare directly between profiles induced by Copaxone® andby the purported generic Polimunol. Based on previous power calculations(using the R package ssize.fdr), to detect differentially-expressedgenes with a fold-change between treatments of as low as 1.3 with 80%power the experiment was designed to include six replicates of eachcondition. The order of sample processing was randomized with respect totreatment in order to avoid creating confounding batch effects.

Cells from a human monocyte cell line (THP-1) were stimulated witheither Copaxone®, purported generics from several manufacturersincluding Polimunol by Synthon, or vehicle control (mannitol) for 6hours. The 6 hour timepoint was selected because the greatest effectsacross all treatments were observed at this timepoint in the previousstudy described above in Example 1. RNA was extracted and expressionprofiled genome-wide using the Affymetrix U133 Plus 2.0 chip. Threebatches of Copaxone® and one batch of Polimunol were comparativelytested in six replicates each. RNA processing was performed byExpression Analysis (NC, USA).

Differentially-expressed probesets were identified across conditionsusing linear models for microarray data (LIMMA). For comparing Copaxone®(“GA”) and purported generic, comparisons were corrected for mannitolcontrol (i.e., [GA vs mannitol] was compared to [purported generic vsmannitol]). Probesets were filtered by calls of presence on the chip forthe relevant samples in the comparison (to be considered present at agiven timepoint, a probeset was required to have on average a call ofpresent or marginal across the relevant samples at that timepoint).Probesets were mapped to genes using the U133 Plus 2.0 chip annotationfrom Affymetrix. Unless otherwise specified, all probesets calledpresent for a gene showed the effect discussed above; where all multipleprobesets were present for a gene, p values are reported for the mostsignificant probeset.

Upregulated and downregulated genes were analyzed separately for pathwayenrichment, using DAVID [Huang, D. W., Sherman, B. T. & Lempicki, R. A.Bioinformatics enrichment tools: paths toward the comprehensivefunctional analysis of large gene lists. Nucleic Acids Res. 37, 1-13(2009)]. Pathway enrichment results were visualized using volcano plots,plotting −log p-values versus enrichment scores. For GA MOA, to obtaintop-gene lists of appropriate size (tens-hundreds) for use with DAVID,an absolute-value fold-change cutoff of 1.5 and p-value cutoff of 1e-3were utilized to obtain gene lists for pathway enrichment. Forcomparisons between GA and Polimunol, upregulated or downregulated geneswith FDR-adjusted p-values<0.05 were used for pathway enrichment. DAVIDruns were conducted on Sep. 12, 2014. Please note that the GO databasesare updated daily (as noted on the GOsite:www.geneontology.org/GO.downloads.ontology.shtml) and thereforeperforming the same enrichments on the same genesets may yield slightlyvarying results depending on the rundate. Pathway p-values may changeslightly between runs conducted at different times; the overall pictureof enriched pathways, however, is expected to remain consistent.

Genes differentially expressed between Copaxone® and mannitol controlare enriched with a variety of pathways in Kegg and GO (molecularfunction (MF), biological process (BP), and cellular component (CC)),many of which affect immunological responses, demonstrating Copaxone'scomplex mechanism of action, as shown in FIG. 23. Pathways enrichedamong top probesets modulated by Copaxone versus mannitol control areshown in Table 12. More than 80% of the pathways that enriched among topupregulated genes in the previous study were also enriched among topupregulated genes in the current study.

As an example at the individual gene level, IL1RN was significantlyupregulated (adjusted p<2.8e-10), as shown in FIG. 24, which isconsistent with the previous study described in Example 1 above. Thisgene encodes for the protein IL-1ra, which inhibits the activities ofpro-inflammatory cytokines IL-1a and IL-1b.

The probeset for IL10, which had been observed to be upregulated byCopaxone® above in Example 1, was called absent in this experiment, butwas nominally upregulated (p<0.029). However, the IL10 receptor IL10RAwas significantly upregulated (for the single probeset for this gene,which was called present) (adjusted p<2.8e-14).

Genes analyzed for pathway enrichment (Table 12), using DAVID (conductedSep. 12, 2014). Performing the same enrichments on the same genesets mayyield slightly varying results depending on the run date (GO databasesare updated daily: www.geneontology.org/GO.downloads.ontology.shtml).

TABLE 12 Human monocyte study: pathways significantly enriched amonggenes significantly upregulated by Copaxone ® relative to mannitol at 6hours Fold Category Term Count % Pvalue List Total Pop Hits Pop TotalEnrichment Bonferroni Benjamini FDR GOTERM_(—) GO:005886~plasma 12135.17 6.53E−20 305 1699 9576 2.236 1.78E−17 1.78E−17 8.60E−17 CC_ALLmembrane GOTERM_(—) GO:0050895~response 127 36.92 4.65E−19 291 1815 87312.099 1.01E−15 1.01E−15 8.07E−16 BP_ALL to stimulus GOTERM_(—)GO:0009605~response 57 16.57 9.39E−17 291 492 8731 3.476 2.42E−131.21E−13 1.89E−13 BP_ALL to external stimulus GOTERM_(—)GO:0009611~response 40 11.63 1.44E−14 291 281 8731 4.271 3.15E−111.05E−11 2.51E−11 BP_ALL to wounding GOTERM_(—) GO:0005887~integral 5315.41 1.31E−13 305 528 9576 3.152 3.57E−11 1.79E−11 1.73E−10 CC_ALL toplasma membrane GOTERM_(—) GO:0031226~intrinsic 53 15.41 2.60E−13 305537 9576 3.099 7.08E−11 2.36E−11 3.42E−10 CC_ALL to plasma membraneGOTERM_(—) GO:0005576~extracellular 59 17.15 6.56E−13 305 662 9576 2.7981.79E−10 4.46E−11 8.64E−10 CC_ALL region GOTERM_(—)GO:0044421~extracellular 39 11.34 1.93E−12 305 324 9576 3.779 5.26E−101.05E−10 2.54E−09 CC_ALL region part GOTERM_(—) GO:0050793~regulation 4613.37 4.84E−13 291 406 8731 3.399 1.06E−09 2.64E−10 8.41E−10 BP_ALL ofdevelopmental process GOTERM_(—) GO:0051239~regulation 50 14.53 1.43E−11291 517 8731 2.902 3.12E−08 6.23E−09 2.48E−08 BP_ALL of multicellularorganismal process GOTERM_(—) GO:0004872~receptor 54 15.70 4.34E−11 297637 9375 2.676 2.57E−08 1.28E−08 6.40E−08 MF_ALL activity GOTERM_(—)GO:0060089~molecular 68 19.77 2.37E−11 297 915 9375 2.346 1.40E−081.40E−08 3.49E−08 MF_ALL transducer activity GOTERM_(—)GO:0004871~signal 68 19.77 2.37E−11 297 915 9375 2.346 1.40E−08 1.40E−083.49E−08 MF_ALL transducer activity GOTERM_(—) GO:004888~transmembrane36 10.47 1.44E−10 297 325 9375 3.497 8.53E−08 2.84E−08 2.12E−07 MF_ALLreceptor activity GOTERM_(—) GO:0001568~blood 25 7.27 8.49E−11 291 1488731 5.068 1.86E−07 3.09E−08 1.48E−07 BP_ALL vessel developmentGOTERM_(—) GO:0044459~plasma 73 21.22 7.32E−10 305 1095 9576 2.0931.99E−07 3.32E−08 9.63E−07 CC_ALL membrane part GOTERM_(—)GO:0048731~system 83 24.13 1.24E−10 291 1231 8731 2.023 2.70E−073.38E−08 2.15E−07 BP_ALL development GOTERM_(—) GO:0048514~blood 23 6.691.43E−10 291 127 8731 5.434 3.12E−07 3.46E−08 2.48E−07 BP_ALL vesselmorphogenesis GOTERM_(—) GO:0001944~vasculature 25 7.27 1.14E−10 291 1508731 5.001 2.48E−07 3.54E−08 1.97E−07 BP_ALL development GOTERM_(—)GO:0006950~response 76 22.09 2.20E−10 291 1089 8731 2.094 4.80E−074.80E−08 3.81E−07 BP_ALL to stress GOTERM_(—) GO:0006955~immune 38 11.054.63E−10 291 356 8731 3.203 1.01E−06 9.19E−08 8.04E−07 BP_ALL responseGOTERM_(—) GO:0006952~defense 35 10.17 6.58E−10 291 311 8731 3.3771.44E−06 1.20E−07 1.14E−06 BP_ALL response GOTERM_(—)GO:0032501~multicellular 112 32.56 1.21E−09 291 1991 8731 1.688 2.64E−062.03E−07 2.10E−06 BP_ALL organismal process GOTERM_(—)GO:0006954~inflammatory 25 7.27 2.58E−09 291 174 8731 4.311 5.64E−063.76E−07 4.48E−06 BP_ALL response GOTERM_(—) GO:0007275~multicellular 9327.03 2.50E−09 291 1544 8731 1.807 5.47E−06 3.90E−07 4.35E−06 BP_ALLorganismal development GOTERM_(—) GO:0040011~locomotion 29 8.43 4.62E−09291 238 8731 3.656 1.01E−05 6.30E−07 8.02E−06 BP_ALL GOTERM_(—)GO:0032502~developmental 100 29.07 5.35E−09 291 1738 8731 1.726 1.17E−056.49E−07 9.30E−06 BP_ALL process GOTERM_(—) GO:0048545~response 19 5.525.22E−09 291 102 8731 5.589 1.14E−05 6.71E−07 9.07E−06 BP_ALL to steroidhormone stimulus GOTERM_(—) GO:0005615~extracellular 27 7.85 2.53E−08305 235 9576 3.607 6.89E−06 9.84E−07 3.34E−05 CC_ALL space GOTERM_(—)GO:0048856~anatomical 84 24.42 8.74E−09 291 1366 8731 1.845 1.91E−051.01E−06 1.52E−05 BP_ALL structure development GOTERM_(—)GO:0048583~regulation 30 8.72 1.29E−08 291 265 8731 3.397 2.82E−051.41E−06 2.24E−05 BP_ALL of response to stimulus GOTERM_(—)GO:0002376~immune 47 13.66 1.94E−08 291 578 8731 2.440 4.25E−05 2.02E−063.38E−05 BP_ALL system process GOTERM_(—) GO:0031012~extracellular 185.23 8.69E−08 305 113 9576 5.001 2.36E−05 2.95E−06 0.0011434 CC_ALLmatrix GOTERM_(—) GO:0001525~angiogenesis 17 4.94 4.00E−08 291 91 87315.605 8.73E−05 3.97E−06 6.95E−05 BP_ALL GOTERM_(—) GO:0051707~response22 6.40 5.14E−08 291 158 8731 4.178 0.00011219 4.88E−06 8.92E−05 BP_ALLto other organism GOTERM_(—) GO:0016477~cell 22 6.40 6.42E−08 291 1608731 4.125 0.00014011 5.84E−06 0.00011144 BP_ALL migration GOTERM_(—)GO:0016020~membrane 169 49.13 1.96E−07 305 3915 9576 1.355 5.33E−055.93E−06 0.00025814 CC_ALL KEGG_(—) hsa04060: Cytokine- 19 5.52 8.99E−08123 109 3163 4.483 9.53E−06 9.53E−06 0.00010084 PATHWAY cytokinereceptor interaction GOTERM_(—) GO:0009653~anatomical 50 14.53 1.18E−07291 675 8731 2.222 0.00025871 9.58E−06 0.00020578 BP_ALL structuremorphogenesis GOTERM_(—) GO:0042221~response 56 16.28 1.17E−07 291 8028731 2.095 0.00025627 9.86E−06 0.00020384 BP_ALL to chemical stimulusGOTERM_(—) GO:0010033~response 39 11.34 1.26E−07 291 457 8731 2.5600.0002761 9.86E−06 0.00021962 BP_ALL to organic substance GOTERM_(—)GO:0048513~organ 62 18.02 1.13E−07 291 532 8731 1.996 0.000246759.87E−06 0.00019627 BP_ALL development GOTERM_(—) GO:0048519~negative 7421.51 1.50E−07 291 1214 8731 1.829 0.00032738 1.13E−05 0.00026041 BP_ALLregulation of biological process GOTERM_(—) GO:0032101~regulation 154.36 1.86E−07 291 77 8731 5.845 0.00040597 1.35E−05 0.00032294 BP_ALL ofresponse to external stimulus GOTERM_(—) GO:0065008~regulation 57 16.571.97E−07 291 836 8731 2.046 0.00042941 1.39E−05 0.0003416 BP_ALL ofbiological quality GOTERM_(—) GO:0005578~proteinaceous 16 4.65 5.27E−07305 100 9576 5.023 0.00014321 1.43E−05 0.00069309 CC_ALL extracellularmatrix GOTERM_(—) GO:0048646~anatomical 25 7.27 2.19E−07 291 218 87313.441 0.00047903 1.50E−05 0.00038107 BP_ALL structure formation involvedin morphogenesis GOTERM_(—) GO:0048870~cell 22 6.40 2.49E−07 291 1738731 3.815 0.00054426 1.65E−05 0.00043298 BP_ALL motility GOTERM_(—)GO:0051674~localization 22 6.40 2.49E−07 291 173 8731 3.815 0.000544261.65E−05 0.00043298 BP_ALL of cell GOTERM_(—) GO:0051094~positive 225.40 2.75E−07 291 174 8731 3.794 0.00060061 1.77E−05 0.00047782 BP_ALLregulation of developmental process GOTERM_(—) GO:0031224~intrinsic 12335.76 1.13E−06 305 2645 9576 1.460 0.00030837 2.80E−05 0.00149255 CC_ALLto membrane GOTERM_(—) GO:0030154~cell 58 16.86 5.18E−07 291 883 87311.971 0.00113121 3.23E−05 0.00090018 BP_ALL differentiation GOTERM_(—)GO:0007166~cell 48 13.35 5.38E−07 291 667 8731 2.159 0.00117393 3.26E−050.0009342 BP_ALL surface receptor linked signal transduction GOTERM_(—)GO:0019955~cytokine 13 3.78 3.43E−07 297 61 9375 6.727 0.000202785.07E−05 0.00050503 MF_ALL binding GOTERM_(—) GO:0042060~wound 16 4.659.16E−07 291 100 8731 4.801 0.00199804 5.41E−05 0.00159067 BP_ALLhealing GOTERM_(—) GO:0006928~cell 27 7.85 1.17E−06 291 273 8731 2.9670.00254332 6.70E−05 0.00202532 BP_ALL motion GOTERM_(—)GO:0022603~regulation 18 5.23 1.40E−06 291 131 8731 4.123 0.003053047.84E−05 0.00243184 BP_ALL of anatomical structure morphogenesisGOTERM_(—) GO:0048518~positive 76 22.09 1.48E−06 291 1335 8731 1.7080.00323049 7.89E−05 0.00257341 BP_ALL regulation of biological processGOTERM_(—) GO:0045597~positive 19 5.52 1.46E−06 291 146 8731 3.9050.00318974 7.99E−05 0.0025409 BP_ALL regulation of cell differentiationGOTERM_(—) GO:0048869~cellular 59 17.15 1.61E−06 291 937 8731 1.8890.00351577 8.39E−05 0.00280106 BP_ALL developmental process GOTERM_(—)GO:0045595~regulation 28 8.14 1.90E−06 291 298 8731 2.819 0.004138589.64E−05 0.00329828 BP_ALL of cell differentiation GOTERM_(—)GO:0065007~biological 189 54.94 2.27E−06 291 4499 8731 1.260 0.004938830.00011252 0.00393762 BP_ALL regulation GOTERM_(—) GO:0009607~response24 6.98 2.33E−06 291 231 8731 3.117 0.00508171 0.00011321 0.00405183BP_ALL to biotic stimulus GOTERM_(—) GO:0016021~integral 117 34.017.05E−06 305 2564 9576 1.433 0.00191674 0.00015987 0.00928437 CC_ALL tomembrane GOTERM_(—) GO:0050789~regulation 181 52.62 6.79E−06 291 43128731 1.259 0.01472889 0.00032252 0.01180067 BP_ALL of biological processGOTERM_(—) GO:0051384~response 10 2.91 7.38E−06 291 42 8731 7.1440.01599922 0.0003431 0.01282663 BP_ALL to glucocorticoid stimulusGOTERM_(—) GO:0002682~regulation 23 6.69 1.05E−05 291 235 8731 2.9370.02269405 0.00047813 0.01825541 BP_ALL of immune system processGOTERM_(—) GO:0031960~response 10 2.91 1.11E−05 291 44 8731 6.8190.02389824 0.00049352 0.01923579 BP_ALL to corticosteroid stimulusGOTERM_(—) GO:0007610~behavior 22 6.40 1.34E−05 291 221 8731 2.9870.02894023 0.00058717 0.02335375 BP_ALL GOTERM_(—) GO:0009617~response14 4.07 1.39E−05 291 95 8731 4.422 0.02982868 0.0005936 0.02408158BP_ALL to bacterium GOTERM_(—) GO:0007626~locomotory 17 4.94 1.51E−05291 140 8731 3.643 0.03243116 0.00063381 0.02621736 BP_ALL behaviorGOTERM_(—) GO:0048523~negative 64 18.60 1.57E−05 291 1127 8731 1.7040.03368346 0.00064628 0.02724712 BP_ALL regulation of cellular processGOTERM_(—) GO:0043627~response 11 3.20 2.08E−05 291 59 8731 5.5940.04438121 0.00084032 0.03609816 BP_ALL to estrogen stimulus GOTERM_(—)GO:0048878~chemical 23 6.69 2.33E−05 291 247 8731 2.794 0.04951740.00092295 0.0403827 BP_ALL homeostasis GOTERM_(—) GO:0019838~growth 113.20 8.31E−05 297 56 9375 6.200 0.0049076 0.00098345 0.01225035 MF_ALLfactor binding GOTERM_(—) GO:0070482~response 13 3.78 2.74E−05 291 878731 4.483 0.05817137 0.00106964 0.04765395 BP_ALL to oxygen levelsGOTERM_(—) GO:0000262~cell 41 11.92 5.68E−05 305 662 9576 1.9450.01533071 0.00118767 0.07473585 CC_ALL fraction GOTERM_(—)GO:0005626~insoluble 34 9.88 6.61E−05 305 508 9576 2.101 0.0178098670.00128276 0.08692732 CC_ALL fraction GOTERM_(—) GO:0006935~chemotaxis13 3.78 3.46E−05 291 89 8731 4.383 0.07280814 0.00132535 0.06020426BP_ALL GOTERM_(—) GO:0042330~taxis 13 3.78 3.46E−05 291 89 8731 4.3830.07280814 0.00132535 0.06010426 BP_ALL GOTERM_(—) GO:0009968~negative16 4.65 3.90E−05 291 135 8731 3.556 0.08171162 0.00146864 0.06777345BP_ALL regulation of signal GOTERM_(—) GO:0014070~response 12 3.494.26E−05 291 77 8731 4.676 0.0888131 0.00152355 0.07394353 BP_ALL toorganic cyclic substance GOTERM_(—) GO:0007165~signal 74 21.51 4.14E−05291 1411 8731 1.574 0.08646755 0.00153165 0.07190035 BP_ALL transductionGOTERM_(—) GO:0048584~positive 16 4.65 4.26E−05 291 136 8731 3.5300.08879912 0.00154866 0.07393134 BP_ALL regulation of response tostimulus GOTERM_(—) GO:0009719~response 22 6.40 5.26E−05 291 242 87312.728 0.10344839 0.00184978 0.09125557 BP_ALL to endogenous stimulusGOTERM_(—) GO:0045765~regulation 8 2.33 6.83E−05 291 32 8731 7.5010.1386353 0.00236604 0.11862156 BP_ALL of angiogenesis GOTERM_(—)GO:0009991~response 16 4.65 7.04E−05 291 142 8731 3.381 0.142606650.00240115 0.12229249 BP_ALL to extracellular stimulus GOTERM_(—)GO:0048522~positive 66 19.19 7.28E−05 291 1234 8731 1.605 0.147019190.00244344 0.12639105 BP_ALL regulation of cellular process GOTERM_(—)GO:0005624~membrane 32 9.30 0.0001466 305 484 9576 2.076 0.039094560.00265509 0.19280628 CC_ALL fraction GOTERM_(—) GO:0044425~membrane 14040.70 0.00016676 305 3420 9576 1.285 0.04435026 0.00283122 0.21929353CC_ALL part GOTERM_(—) GO:0001666~response 12 3.49 8.62E−05 291 83 87314.338 0.17161099 0.00284855 0.14962549 BP_ALL to hypoxia GOTERM_(—)GO:0050776~regulation 15 4.36 9.15E−05 291 123 8731 3.489 0.181063730.00297689 0.15873903 BP_ALL of immune response GOTERM_(—)GO:0010648~negative 16 4.65 9.69E−05 291 146 8731 3.288 0.190777350.00306314 0.16821347 BP_ALL regulation of cell communication GOTERM_(—)GO:0048585~negative 10 2.91 9.62E−05 291 57 8731 5.264 0.199549020.00308588 0.16700917 BP_ALL regulation of response to stimulusGOTERM_(—) GO:0031099~regeneration 8 2.33 0.00010316 291 34 8731 7.0600.20173321 0.00321357 0.17903588 BP_ALL GOTERM_(—) GO:0009725~response20 5.81 0.0001064 291 217 8731 2.765 0.20736027 0.0032677 0.18465182BP_ALL to hormone stimulus GOTERM_(—) GO:0050801~ion 19 5.52 0.00011383291 200 8731 2.850 0.22011692 0.00344698 0.19753113 BP_ALL homeostasisGOTERM_(—) GO:0007155~cell 26 7.56 0.00011726 291 334 8731 2.3360.22594061 0.00350216 0.20348045 BP_ALL adhesion GOTERM_(—)GO:0022610~biological 26 7.56 0.00012311 291 335 8731 2.329 0.235769260.00362699 0.21362257 BP_ALL adhesion GOTERM_(—) GO:0006873~cellular 185.23 0.00016537 291 163 8731 2.873 0.30315535 0.00480433 0.28685303BP_ALL ion homeostasis GOTERM_(—) GO:0055082~cellular 18 5.23 0.00017635291 189 8731 2.857 0.31967946 0.00505548 0.30588293 BP_ALL chemicalhomeostatis GOTERM_(—) GO:0002684~positive 15 4.36 0.00018897 291 1388731 3.261 0.33816687 0.00534594 0.32772523 BP_ALL regulation of immunesystem process GOTERM_(—) GO:0002703~regulation 8 2.33 0.00021596 291 388731 6.317 0.37607009 0.00595331 0.37446511 BP_ALL of leukocyte mediatedimmunity GOTERM_(—) GO:0032496~response 9 2.62 0.00021432 291 50 87315.401 0.37382152 0.00598356 0.37161469 BP_ALL to lipopolysaccharideKEGG_(—) hsa04640: Hematopoietic 9 2.62 0.00012756 123 41 3163 5.6450.01343153 0.00673847 0.14304552 PATHWAY cell lineage GOTERM_(—)GO:0002822~regulation 8 2.33 0.00025583 291 39 8731 6.155 0.428106160.00696069 0.44344237 BP_ALL of adaptive immune response based onsomatic recombination of immune receptors built from immunoglobulinsuperfamily domains GOTERM_(—) GO:0051704~multi- 30 8.72 0.00026472 291436 8731 2.064 0.43910546 0.00711313 0.45881825 BP_ALL organism processGOTERM_(—) GO:0003008~system 31 9.01 0.00029081 291 460 8731 2.0220.47018397 0.00771672 0.50393593 BP_ALL process GOTERM_(—)GO:0050794~regulation 168 48.84 0.00029607 291 4148 8731 1.2150.47623627 0.00776147 0.51302706 BP_ALL of cellular process GOTERM_(—)GO:0002819~regulation 8 2.33 0.00030141 291 40 8731 6.001 0.482307320.00780714 0.52225166 BP_ALL of adaptive immune response GOTERM_(—)GO:0031225~anchored 11 3.20 0.00049512 305 89 9576 3.880 0.126028060.00789263 0.64978292 CC_ALL to membrane GOTERM_(—)GO:0042592~homeostatic 29 8.43 0.00036654 291 423 8731 2.057 0.550978160.00937553 0.63477609 BP_ALL process GOTERM_(—)GO:0015718~monocarboxylic 7 2.03 0.00038604 291 30 8731 7.001 0.569698760.00975755 0.66842859 BP_ALL acid transport GOTERM_(—)GO:0040012~regulation 13 3.78 0.00041686 291 115 8731 3.392 0.597723960.01041227 0.72161898 BP_ALL of locomotion GOTERM_(—)GO:0006357~regulation 32 9.30 0.00043124 291 493 8731 1.947 0.610168790.01064792 0.74642831 BP_ALL of transcription from RNA polymerase IIpromoter GOTERM_(—) GO:0031328~positive 29 8.43 0.00050989 291 432 87312.014 0.67171554 0.01243745 0.88197876 BP_ALL regulation of cellularbiosynthetic process GOTERM_(—) GO:0050878~regulation 10 2.91 0.00053053291 71 8731 4.226 0.68619313 0.01279497 0.91752731 BP_ALL of body fluidGOTERM_(—) GO:0010876~lipid 12 3.49 0.00054417 291 102 8731 3.5300.69540799 0.01297858 0.94101129 BP_ALL localization GOTERM_(—)GO:0050865~regulation 12 3.49 0.00059161 291 103 8731 3.496 0.725407160.01395032 1.02266381 BP_ALL of cell activation GOTERM_(—)GO:0002237~response 9 2.62 0.00060803 291 58 8731 4.656 0.735081270.01418162 1.05089343 BP_ALL to molecule of bacterial origin GOTERM_(—)GO:0030247~polysaccharide 10 2.91 0.00014598 297 63 9375 5.0100.08279861 0.01430145 0.21499395 MF_ALL binding GOTERM_(—)GO:0001871~pattern 10 2.91 0.00014598 297 63 9375 5.010 0.082798610.01430145 0.21499395 MF_ALL binding GOTERM_(—) GO:0042127~regulation 319.01 0.00063941 291 482 8731 1.930 0.75264313 0.01475101 1.10485745BP_ALL of cell proliferation GOTERM_(—) GO:0009891~positive 29 8.430.00066254 291 439 8731 1.982 0.76483615 0.01512107 1.14460859 BP_ALLregulation of biosynthetic process GOTERM_(—) GO:0044057~regulation 144.07 0.00075021 291 140 8731 3.000 0.80584037 0.01692876 1.29513516BP_ALL of system process GOTERM_(—) GO:0002697~regulation 9 2.620.00076637 291 60 8731 4.501 0.81257953 0.01711373 1.32286309 BP_ALL ofimmune effector GOTERM_(—) GO:0046983~protein 26 7.56 0.00020881 297 3649375 2.255 0.11628999 0.01750586 0.30738349 MF_ALL dimerization activityGOTERM_(—) GO:0051270~regulation 13 3.78 0.00088686 291 125 8731 3.1200.8559733 0.01957882 1.52932924 BP_ALL of cell motion GOTERM_(—)GO:0007167~enzyme 17 4.94 0.00094775 291 199 8731 2.563 0.873924380.02070065 1.63352589 BP_ALL linked receptor protein signaling pathwayGOTERM_(—) GO:0009986~cell 15 4.36 0.00141943 305 176 9576 2.6760.3204743 0.02123574 1.85238613 CC_ALL surface GOTERM_(—)GO:0019725~cellular 20 5.81 0.0009974 291 259 8731 2.317 0.886891340.02155829 1.71839807 BP_ALL homeostasis GOTERM_(—)GO:0009966~regulation 35 10.17 0.00102968 291 588 8731 1.786 0.894597530.02203062 1.7735386 BP_ALL of signal transduction GOTERM_(—)GO:0032879~regulation 24 6.98 0.00107922 291 344 8731 2.093 0.905418060.02242069 1.85812337 BP_ALL of localization GOTERM_(—)GO:0002683~negative 8 2.33 0.001076 291 49 8731 4.899 0.904748920.02256898 1.85262047 BP_ALL regulation of immune system processGOTERM_(—) GO:0006869~lipid 11 3.20 0.00107471 291 94 8731 3.5110.90448101 0.0227608 1.85042799 BP_ALL transport GOTERM_(—)GO:0007399~nervous 34 9.88 0.00117602 291 569 8731 1.793 0.923459530.02395313 2.02318447 BP_ALL system development GOTERM_(—)GO:0007154~cell 24 6.98 0.00116651 291 346 8731 2.081 0.921851990.02398529 2.0069868 BP_ALL communication GOTERM_(—)GO:0001570~vasculogenesis 6 1.74 0.00120076 291 25 8731 7.201 0.92749060.02422547 2.06533461 BP_ALL GOTERM_(—) GO:0008284~positive 19 5.520.00126607 291 244 8731 2.136 0.93714055 0.02529364 2.17650973 BP_ALLregulation of cell proliferation GOTERM_(—) GO:0008285~negative 18 5.230.00132516 291 225 8731 2.400 0.94475993 0.02575327 2.2769872 BP_ALLregulation of cell proliferation GOTERM_(—) GO:0042981~regulation 3510.17 0.00131483 291 596 8731 1.762 0.94349817 0.02578432 2.25943273BP_ALL of apoptosis GOTERM_(—) GO:0002696~positive 9 2.62 0.00131011 29165 8731 4.154 0.94291175 0.02592551 2.25140603 BP_ALL regulation ofleukocyte activation GOTERM GO:0002694~regulation 11 3.20 0.00136994 29197 8731 3.402 0.9499138 0.02637809 2.35308046 BP_ALL of leukocyteactivation GOTERM_(—) GO:0008360~regulation 7 2.03 0.00143618 291 388731 5.527 0.95666858 0.02739544 2.4655229 BP_ALL of cell shapeGOTERM_(—) GO:0051173~positive 27 7.85 0.00152867 291 419 8731 1.9330.96460461 0.02863568 2.62231934 BP_ALL regulation of nitrogen compoundmetabolic process GOTERM_(—) GO:0043067~regulation 35 10.17 0.00151875291 602 8731 1.744 0.96382789 0.02869828 2.6055065 BP_ALL of programmedcell death GOTERM_(—) GO:0010941~regulation 35 10.17 0.00162481 291 6048731 1.739 0.97131776 0.03015225 2.78505643 BP_ALL of cell deathGOTERM_(—) GO:0050727~regulation 7 2.03 0.00165079 291 39 8731 5.3850.97290246 0.03036957 2.82898994 BP_ALL of inflammatory GOTERM_(—)GO:0050930~induction 4 1.16 0.00179385 291 8 8731 15.002 0.980184320.03268511 3.07055936 BP_ALL of positive chemotaxis GOTERM_(—)GO:0010646~regulation 37 10.76 0.00194382 291 658 8731 1.687 0.985727630.03450973 3.32320019 BP_ALL of cell communication GOTERM_(—)GO:0050867~positive 9 2.62 0.0019358 291 69 8731 3.913 0.985474950.03465108 3.30970571 BP_ALL regulation of cell activation GOTERM_(—)GO:0080134~regulation 15 4.36 0.00192655 291 174 8731 2.587 0.985177930.03477294 3.29413758 BP_ALL of response to stress GOTERM_(—)GO:0001501~skeletal 14 4.07 0.00202877 291 156 8731 2.693 0.988148960.03570233 3.46603944 BP_ALL system development GOTERM_(—)GO:0009615~response 9 2.62 0.00212404 291 70 8731 3.858 0.990379370.03705101 3.62598828 BP_ALL to virus GOTERM_(—) GO:0009888~tissue 226.40 0.00215578 291 319 8731 2.069 0.99102486 0.03729713 3.67920761BP_ALL development GOTERM_(—) GO:0055066~di, 12 3.49 0.00223579 291 1218731 2.976 0.9924667 0.03835256 3.81327117 BP_ALL tri-valent inorganiccation homeostasis GOTERM_(—) GO:0022604~regulation 10 2.91 0.00230132291 87 8731 3.449 0.99347346 0.03914863 3.92295161 BP_ALL of cellmorphogenesis GOTERM_(—) GO:0042493~response 13 3.78 0.00236067 291 1408731 2.786 0.99426863 0.03952428 4.02217244 BP_ALL to drug GOTERM_(—)GO:0035295~tube 12 3.49 0.00238661 291 122 8731 2.951 0.994584990.03964677 4.06550921 BP_ALL development GOTERM_(—) GO:0043066~negative19 5.52 0.0023525 291 258 8731 2.210 0.99416515 0.03969391 4.0085168BP_ALL regulation of apoptosis GOTERM_(—) GO:0005125~cytokine 9 2.620.00055115 297 60 9375 4.735 0.27846423 0.03997568 0.80944805 MF_ALLactivity GOTERM_(—) GO:0048146~positive 5 1.45 0.00252304 291 18 87318.334 0.99598326 0.04155265 4.2931463 BP_ALL regulation of GOTERM_(—)GO:0044420~extracellular 7 2.03 0.00313139 305 46 9576 4.778 0.573896940.04175683 4.04432272 CC_ALL matrix part KEGG_(—) hsa04610: Complement 61.74 0.00122148 123 22 3163 7.013 0.12151451 0.04226609 1.36209977PATHWAY and coagulation cascades GOTERM_(—) GO:0005604~basment 6 1.740.00310557 305 32 9576 5.887 0.57088513 0.04355111 4.01160983 CC_ALLmembrane GOTERM_(—) GO:0043069~negative 19 5.52 0.00267451 291 261 87312.184 0.99711711 0.04366649 4.5452809 BP_ALL regulation of programmedcell death GOTERM_(—) GO:0060548~negative 19 5.52 0.00277099 291 2628731 2.176 0.99766616 0.04487296 4.70554415 BP_ALL regulation of celldeath GOTERM_(—) GO:0050671~positive 6 1.74 0.00281214 291 30 8731 6.0010.9978673 0.04519043 4.77382529 BP_ALL regulation of lymphocyteproliferation GOTERM_(—) GO:0070665~positive 6 1.74 0.00281214 291 308731 6.001 0.9978673 0.04519043 4.77382529 BP_ALL regulation ofleukocyte proliferation GOTERM_(—) GO:0032946~positive 6 1.74 0.00281214291 30 8731 6.001 0.9978673 0.04519043 4.77382529 BP_ALL regulation ofmononuclear cell proliferation GOTERM_(—) GO:0030141~secretory 10 2.910.00359451 305 97 9576 3.237 0.62448874 0.04557029 4.62946073 CC_ALLgranule GOTERM_(—) GO:0010628~positive 24 6.98 0.00297411 291 372 87311.936 0.99850427 0.04704368 5.04213471 BP_ALL regulation of geneexpression GOTERM_(—) GO:0010557~positive 26 7.56 0.00295976 291 4178731 1.871 0.99845649 0.04716276 5.01838762 BP_ALL regulation ofmacromolecule biosynthetic process GOTERM_(—) GO:0051241~negative 9 2.620.00302532 291 74 8731 3.649 0.99866299 0.04749198 5.12681765 BP_ALLregulation of multicellular organismal process GOTERM_(—)GO:0007204~elevation 7 2.03 0.00310921 291 44 8731 4.773 0.998887430.04843088 5.26537775 BP_ALL of cytosolic calcium ion concentrationGOTERM_(—) GO:0001503~ossification 8 2.33 0.00322266 291 59 8731 4.0680.99913229 0.04980154 5.45247258 BP_ALL Category Genes GOTERM_(—)210495_X_AT, 229221_AT, 223723_AT, 210136_AT, 212298_AT, 209555_S_AT,212014_X_AT, CC_ALL 216834_AT, 203923_S_AT, 211066_X_AT, 210916_S_AT,216971_S_AT, 219412_AT, 207674_AT, 202828_S_AT, 230360_AT, 236561_AT,226545_AT, 201925_AT, 217173_S_AT, 204489_S_AT, 207610_S_AT, 220307_AT,212099_AT, 211307_S_AT, 223303_AT, 201590_X_AT, 232549_AT, 203922_S_AT,229937_X_AT, 214830_AT, 1552914_A_AT, 203104_AT, 212977_AT, 202756_S_AT,228766_AT, 203508_AT, 230925_AT, 210845_S_AT, 243556_AT, 206033_S_AT,201005_AT, 201242_S_AT, 233220_AT, 242907_AT, 207819_S_AT, 224678_AT,209122_AT, 214211_AT, 217252_AT, 160020_AT, 208926_AT, 214297_AT,210233_AT, 218910_AT, 211719_X_AT, 209949_AT, 214866_AT, 223501_AT,205534_AT, 34210_AT, 205099_S_AT, 209994_S_AT, 1557905_S_AT, 228754_AT,209670_AT, 238542_AT, 215836_S_AT, 217678_AT, 205717_X_AT, 217078_S_AT,209047_AT, 238581_AT, 201739_AT, 1554992_AT, 209906_AT, 221840_AT,211030_S_AT, 205920_AT, 208121_S_AT, 211676_S_AT, 1554600_S_AT,238669_AT, 235295_AT, 203233_AT, 204105_S_AT, 201313_AT, 219994_AT,201125_S_AT, 217279_X_AT, 201243_S_AT, 204912_AT, 201069_AT,211924_S_AT, 222877_AT, 241938_AT, 203217_S_AT, 209079_X_AT,206488_S_AT, 206171_AT, 220066_AT, 228640_AT, 203939_AT, 205542_AT,243894_AT, 204359_AT, 213428_S_AT, 205891_AT, 204736_S_AT, 203665_AT,204450_S_AT, 202748_AT, 208816_X_AT, 239519_AT, 209835_X_AT 208161_S_AT,209921_AT, 204715_AT, 223502_S_AT, 212086_X_AT, 220484_AT, 203887_S_AT223939_AT, 209146_AT, 202968_S_AT, 209392_AT, 241773_AT, 224859_AT,209993_AT, 201324_AT, 201012_AT, 212464_S_AT, 216442_X_AT, 213503_X_AT,227240_AT, 210427_X_AT, 214724_AT, 226218_AT, 204991_AT, 200748_S_AT,227107_AT, 204401_AT, 211661_X_AT, 222062_AT, 202686_S_AT, 203548_S_AT,223092_AT, 225188_AT, 217552_X_AT, 202827_S_AT, 205419_AT, 202071_AT,210839_AT, 235299_AT, 224701_AT, 215332_AT, 202827_S_AT, 220313_AT,205718_AT, 203888_AT, 212372_AT, 203935_AT, 223796_AT, 212049_AT,212096_S_AT, 210258_AT, 1556583_A_AT, 229797_AT, 218223_S_AT, 226302_AT,203411_S_AT, 241929_AT, 210173_AT, 202067_S_AT, 219434_AT, 215688_AT,205098_AT GOTERM_(—) 201464_X_AT, 202540_S_AT, 203465_AT, 219028_AT,212298_AT, 204972_AT, 212014_X_AT, 221731_X_AT, BP_ALL 216834_AT,203923_S_AT, 207674_AT, 211068_AT, 205067_AT, 202859_X_AT, 201170_S_AT,217173_S_AT, 204489_S_AT, 204620_S_AT, 211307_S_AT, 201147_S_AT,201565_S_AT, 203922_S_AT, 2218715_AT, 1552914_A_AT, 213562_S_AT,1555832_S_AT, 223876_AT, 2064495_S_AT, 208435_S_AT, 234211_AT,216748_S_AT, 63825_AT, 205463_S_AT, 1405_I_AT, 201566_X_AT, 209949_AT,211719_X_AT, 223501_AT, 229830_AT, 204058_AT, 202086_AT, 205093_S_AT,1557905_S_AT, 235944_AT, 238542_AT, 209670_AT, 209047_AT, 217074_S_AT,201150_S_AT, 2011

_S_AT, 155

_AT, 217757_AT, 20405

_S_AT, 2132

1_AT, 201626_AT, 212

_S_AT 23

669_AT, 2

223_AT, 3702

_AT, 201243_S_AT, 217757_AT, 20

_AT, 2

77_AT, 20270

_S_AT, 201041_S_AT, 222

3_AT, 202434_S_AT, 212657_S_AT, 2064

_S_AT, 220066_AT, 200878_AT, 203

_AT, 205

1_AT, 23445

_S_AT, 20274

_AT, 23

19_AT, 20

35_X_AT, 225116_AT, 204715_AT, 22

502_S_AT, 201466_S_AT, 2

7_S_AT, 2029

_S_AT, 20

37_S_AT, 20253

_S_AT, 23621

_AT, 21

4_S_AT, 2007

_S_AT, 204401_AT, 202686_S_AT, 2220

2_AT, 210512_S_AT, 217552_X_AT, 211527_X_AT, 203140_AT, 220266_S_AT,202241_AT, 202044_X_AT, 20

925_AT, 15565

_A_AT, 229797_AT, 215

_AT, 2010

_AT, 229221_AT, 210

95_X_AT, 22013

_AT, 209555_S_AT, 202435_S_AT, 2162

3_S_AT, 201473_AT, 203074_AT, 220916_S_AT, 201471_S_AT, 2

573

_AT, 20

2_AT, 20282

_S_AT, 236361_AT, 2022

_S_AT, 20

27_S_AT, 201925_S_AT, 22

0_AT, 213577_AT, 229937_X_AT, 225115_AT, 20

50

_AT, 210

45_S_AT, 203005_AT, 201242_S_AT, 20

1_S_AT, 233220_AT, 207

9_S_AT, 242907_AT, 209122_AT, 213293_S_AT, 1

0020_AT, 237252_AT, 212171_X_AT,

02_AT 230233_AT, 2148

_AT, 20

566_AT, 20

4_S_AT, 1552690_A_AT, 23

818_X_AT, 21767

_AT, 2214

3_AT, 20

436_S_AT, 23

_AT, 20

06_AT, 20172

_AT, 20

21

_AT, 20276

_AT, 224606_AT, 210513_S_AT 215646_S_AT, 204619_S_AT, 233295_AT,201313_AT, 215451_AT, 2250

7_AT, 217279_X_AT, 201627_S_AT, 20106

_AT, 205552_S_AT, 221341_S_AT, 211524_S_AT, 212

_AT, 213763_AT, 206171_AT, 202

14_AT, 204490_S_AT, 202436_S_AT, 20114

_S_AT, 20

21_AT, 20

157_AT, 22

7_AT, 204

_AT, 220

4_AT, 225368_AT, 20

2_AT, 22

_AT, 201

25_S_AT, 20

_AT, 201012_AT, 2124

4_S_AT, 216442_X_AT, 20

22_X_AT, 241722_X_AT, 227107_AT, 221

1_X_AT, 20

27_S_AT, 22

0

2_AT, 22

1

_S_AT,

71

0_AT, 205415_AT, 15

2467_AT, 210

_S_AT, 20

65_S_AT,

571_S_AT, 20

55_AT, 15

2553_A_AT, 20

1

_AT,

02437_S_AT, 2020

_S_AT, 212372_AT, 20

_AT, 227

7_AT, 217222_S_AT,

56575

_A_AT, 241

29_AT, 202067_S_AT, 215434_AT,

11571_S_AT GOTERM_(—) 201464_X_AT, 229221_AT, 201465_S_AT, 210495_X_AT,21229

_AT, 209555_S_AT, 216243_S_AT, BP_ALL 212014_X_AT, 221731_X_AT,201473_AT, 203923_S_AT, 203074_AT, 210916_S_AT, 235739_AT, 20

960_S_AT, 202828_S_AT, 205067_AT, 202859_X_AT, 202284_S_AT, 209827_S_AT,201925_S_AT, 201170_S_AT, 204489_S_AT, 228490_AT, 204620_S_AT,201147_S_AT, 203922_S_AT, 221815_AT, 1555832_S_AT, 228766_AT, 203508_AT,210

45_S_AT, 201005_AT, 208961_S_AT, 233220_AT, 237252_AT, 160020_AT,216248_S_AT, 63825_AT, 39402_AT, 205463_S_AT, 210233_AT, 1405_I_AT, 214

66_AT, 211719_X_AT, 229830_AT, 205099_S_AT, 205566_AT, 1557905_S_AT,235944_AT, 221463_AT, 208436_S_AT, 201150_S_AT, 201148_S_AT, 209906_AT,217757_AT, 213281_AT, 224606_AT, 204619_S_AT, 215646_S_AT, 217279_X_AT,37152_AT, 221841_S_AT, 211924_S_AT, 222877_AT, 201041_S_AT, 212657_S_AT,206488_S_AT, 206171_AT, 220066_AT, 205891_AT, 203665_AT, 204490_S_AT,201149_S_AT, 239519_AT, 209835_X_AT, 206157_AT, 201466_S_AT, 225337_AT,204035_AT, 203887_S_AT, 209392_AT, 201012_AT, 212464_S_AT, 216442_X_AT,204622_X_AT, 211661_X_AT, 202686_S_AT, 217552_X_AT, 202827_S_AT,87100_AT, 210839_S_AT, 204465_S_AT, 220266_S_AT, 204655_AT,1552553_A_AT, 209189_AT, 201044_X_AT, 203888_AT, 212372_AT, 203935_AT,1556583_A_AT, 227697_AT, 1555759_A_AT, 241929_AT, 211571_S_AT, 205098_ATGOTERM_(—) 229221_AT, 210495_X_AT, 37152_AT, 212298_AT, 209555_S_AT,216243_S_AT, 211924_S_AT, BP_ALL 212014_X_AT, 221731_X_AT, 203923_S_AT,203074_AT, 210016_S_AT, 212657_S_AT, 206488_S_AT, 20

960_S_AT, 206171_AT, 205067_AT, 202859_X_AT, 201925_S_AT, 204489_S_AT,22

490_AT, 203665_AT, 204490_S_AT, 204620_S_AT, 201149_S_AT, 201147_S_AT,239519_AT, 209835_X_AT, 203922_S_AT, 206157_AT, 221815_AT, 225337_AT,204035_AT, 203887_S_AT, 1555832_S_AT, 228766_AT, 203508_AT, 210845_S_AT,201005_AT, 208961_S_AT, 201012_AT, 212464_S_AT, 237252_AT, 216442_X_AT,39402_AT, 63825_AT, 205463_S_AT, 210233_AT, 1405_I_AT, 214866_AT,211719_X_AT, 229830_AT, 205099_S_AT, 211661_X_AT, 205566_AT,1557905_S_AT, 235944_AT, 217552_X_AT, 208436_S_AT, 221463_AT, 87100_AT,201150_S_AT, 204465_S_AT, 201148_S_AT, 209906_AT, 217757_AT, 224606_AT,204655_AT, 1552553_A_AT, 209159_AT, 215646_S_AT, 204619_S_AT, 203888_AT,212372_AT, 203935_AT, 1555759_A_AT, 241929_AT, 211571_S_AT, 205098_ATGOTERM_(—) 223723_AT, 229221_AT, 209555_S_AT, 212014_X_AT, 203923_S_AT,205217_S_AT, 210916_S_AT, CC_ALL 207674_AT, 206488_S_AT, 206171_AT,202828_S_AT, 236561_AT, 228640_AT, 201925_S_AT, 205542_AT, 217173_S_AT,204489_S_AT, 204359_AT, 204736_S_AT, 205

91_AT, 204490_S_AT, 211307_S_AT, 209

35_X_AT, 208161_S_AT, 203922_S_AT, 203104_AT, 202756_S_AT, 203887_S_AT,228766_AT, 241773_AT, 209392_AT, 201005_AT, 201242_S_AT, 233230_AT,207819_S_AT, 160020_AT, 237252_AT, 214297_AT, 210333_AT, 22

910_AT, 209949_AT, 205534_AT, 204661_AT, 34210_AT, 205099_S_AT,204401_AT, 211661_X_AT, 1557905_S_AT, 202

86_S_AT, 222062_AT, 22

754_AT, 209670_AT, 202827_S_AT, 217552_X_AT, 22

092_AT, 209047_AT, 205419_AT, 202071_AT, 210839_S_AT, 209906_AT,202068_S_AT, 205

20_AT, 211030_S_AT, 211676_S_AT, 208121_S_AT, 205718_AT, 203888_AT,203935_AT, 203253_AT, 204105_S_AT, 1556583_A_AT, 225302_AT, 210173_AT,241929_AT, 217279_X_AT, 201125_S_AT, 202067_S_AT, 201243_S_AT, 205098_ATGOTERM_(—) 223723_AT, 229221_AT, 209555_S_AT, 212014_X_AT, 203923_S_AT,203217_S_AT, 210916_S_AT, CC_ALL 207674_AT, 206488_S_AT, 206171_AT,202828_S_AT, 236561_AT, 228640_AT, 201925_S_AT, 205542_AT, 217173_S_AT,204489_S_AT, 204359_AT, 204736_S_AT, 205891_AT, 204490_S_AT,211307_S_AT, 209835_X_AT, 208161_S_AT, 203922_S_AT, 203104_AT,202756_S_AT, 203887_S_AT, 228766_AT, 241773_AT, 209392_AT, 201005_AT,201242_S_AT, 233220_AT, 207819_S_AT, 160020_AT, 237252_AT, 214297_AT,210233_AT, 228910_AT, 209949_AT, 205534_AT, 204661_AT, 34210_AT,205099_S_AT, 204401_AT, 211661_X_AT, 1557905_S_AT, 202686_S_AT,222062_AT, 228754_AT, 209670_AT, 202827_S_AT, 217552_X_AT, 223092_AT,209047_AT, 205419_AT, 202071_AT, 210839_S_AT, 209906_AT, 202068_S_AT,205920_AT, 211030_S_AT, 211676_S_AT, 208121_S_AT, 205718_AT, 203888_AT,203935_AT, 203233_AT, 204105_S_AT, 1556583_A_AT, 226302_AT, 210173_AT,241929_AT, 217279_X_AT, 201125_S_AT, 202067_S_AT, 201243_S_AT, 205098_ATGOTERM_(—) 229221_AT, 223723_AT, 210495_X_AT, 212298_AT, 216243_S_AT,212014_X_AT, 221731_X_AT, CC_ALL 210916_S_AT, 207674_AT, 202828_S_AT,205067_AT, 228648_AT, 202859_X_AT, 226545_AT, 209827_S_AT, 217173_S_AT,204489_S_AT, 204620_S_AT, 211307_S_AT, 201147_S_AT, 201590_X_AT,202756_S_AT, 205495_S_AT, 204834_AT, 203508_AT, 228873_AT, 210845_S_AT,210095_S_AT, 209122_AT, 237252_AT, 160020_AT, 212171_X_AT, 39402_AT,205463_S_AT, 210233_AT, 1405_I_AT, 211719_X_AT, 214866_AT, 223501_AT,229830_AT, 1557905_S_AT, 206835_AT, 238542_AT, 235944_AT, 221463_AT,201150_S_AT, 201148_S_AT, 217757_AT, 229004_AT, 204619_S_AT,215646_S_AT, 210513_S_AT, 203233_AT, 202087_S_AT, 216546_S_AT,217279_X_AT, 201069_AT, 211924_S_AT, 204222_S_AT, 212657_S_AT,203665_AT, 213428_S_AT, 204359_AT, 204490_S_AT, 208816_X_AT,201149_S_AT, 239519_AT, 209835_X_AT, 212190_AT, 206157_AT, 223502_S_AT,212143_S_AT, 202458_AT, 204035_AT, 225955_AT, 203887_S_AT, 228762_AT,209392_AT, 212464_S_AT, 216442_X_AT, 213503_X_AT, 210427_X_AT,226218_AT, 203940_S_AT, 227265_AT, 219908_AT, 203548_S_AT, 210512_S_AT,202827_S_AT, 225186_S_AT, 211527_X_AT, 204475_AT, 210839_S_AT,204655_AT, 202068_S_AT, 203888_AT, 1555759_A_AT, 219434_AT, 202067_S_AT,211571_S_AT GOTERM_(—) 229223_AT, 210495_X_AT, 201069_AT, 216243_S_AT,212014_X_AT, 221731_X_AT, 210916_S_AT, CC_ALL 212657_S_AT, 202828_S_AT,205067_AT, 202859_X_AT, 226545_AT, 209827_S_AT, 217173_S_AT,204489_S_AT, 203665_AT, 204359_AT, 213428_S_AT, 204490_S_AT,208816_X_AT, 204620_S_AT, 201149_S_AT, 201147_S_AT, 209835_X_AT,201590_X_AT, 212190_AT, 223502_S_AT, 212143_S_AT, 204035_AT,202756_S_AT, 203887_S_AT, 205495_S_AT, 204834_AT, 228873_AT,210095_S_AT, 212464_S_AT, 160020_AT, 237252_AT, 216442_X_AT,212171_X_AT, 213503_X_AT, 39402_AT, 205463_S_AT, 1405_I_AT, 210427_X_AT,211719_X_AT, 223501_AT, 229830_AT, 1557905_S_AT, 203940_S_AT, 227265_AT,238542_AT, 203548_S_AT, 235944_AT, 219908_AT, 210512_S_AT, 202827_S_AT,221463_AT, 211527_X_AT, 204475_AT, 202150_S_AT, 201148_S_AT, 217757_AT,229004_AT, 204655_AT, 210513_S_AT, 215646_S_AT, 204619_S_AT,202068_S_AT, 203888_AT, 1555759_A_AT, 216546_S_AT, 217279_X_AT,202067_S_AT, 211571_S_AT GOTERM_(—) 201464_X_AT, 201465_S_AT,210495_X_AT, 37152_AT, 212298_AT, 210136_AT, 209555_S_AT, BP_ALL227948_AT, 221841_S_AT, 201473_AT, 204923_AT, 206488_S_AT, 1566901_AT,214255_AT, 205067_AT, 236561_AT, 1569149_AT, 216017_S_AT, 203665_AT,205891_AT, 204998_S_AT, 212099_AT, 201565_S_AT, 239519_AT, 201466_S_AT,1552914_A_AT, 212143_S_AT, 215602_AT, 228766_AT, 208937_S_AT, 205312_AT,224859_AT, 210095_S_AT, 212464_S_AT, 216442_X_AT, 212171_X_AT, 39402_AT,1405_I_AT, 201566_X_AT, 211719_X_AT, 226218_AT, 202191_S_AT,218559_S_AT, 206835_AT, 222062_AT, 203940_S_AT, 200921_S_AT,203548_S_AT, 210512_S_AT, 223092_AT, 222670_S_AT, 200920_S_AT,211527_X_AT, 203751_X_AT, 203140_AT, 220266_S_AT, 220935_S_AT,213281_AT, 204655_AT, 210513_S_AT, 1564754_X_AT, 212372_AT, 203935_AT,1565752_AT, 203233_AT, 204105_S_AT, 227697_AT, 203752_S_AT, 219257_S_AT,212803_AT, 1555759_A_AT, 241929_AT GOTERM_(—) 201464_X_AT, 201465_S_AT,210136_AT, 212298_AT, 204923_AT, 235739_AT, 240665_AT, BP_ALL 206171_AT,1566901_AT, 205067_AT, 236561_AT, 220066_AT, 200878_AT, 201170_S_AT,1569149_AT, 216017_S_AT, 205891_AT, 203665_AT, 204998_S_AT, 208816_X_AT,212099_AT, 201565_S_AT, 239519_AT, 201590_X_AT, 204715_AT, 201466_S_AT,1552914_A_AT, 212143_S_AT, 205312_AT, 208937_S_AT, 224859_AT,210095_S_AT, 216248_S_AT, 213503_X_AT, 212171_X_AT, 39402_AT,204622_X_AT, 205463_S_AT, 1405_I_AT, 201566_X_AT, 210427_X_AT,226218_AT, 218934_S_AT, 229830_AT, 218559_S_AT, 227107_AT, 206835_AT,222062_AT, 203940_S_AT, 200921_S_AT, 222670_S_AT, 210512_S_AT,223092_AT, 200920_S_AT, 202071_AT, 211527_X_AT, 1562467_AT, 203751_X_AT,1554992_AT, 203140_AT, 213281_AT, 220935_S_AT, 204655_AT, 210513_S_AT,238669_AT, 235295_AT, 203935_AT, 203233_AT, 204105_S_AT, 1556583_A_AT,203752_S_AT, 219257_S_AT, 212803_AT, 1555759_A_AT, 215688_AT GOTERM_(—)204912_AT, 229221_AT, 37152_AT, 212298_AT, 209555_S_AT, 216243_S_AT,211924_S_AT, MF_ALL 212014_X_AT, 222877_AT, 210916_S_AT, 211352_S_AT,235739_AT, 212657_S_AT, 207674_AT, 206488_S_AT, 206171_AT, 242871_AT,236561_AT, 217173_S_AT, 204489_S_AT, 205891_AT, 204490_S_AT,207610_S_AT, 220307_AT, 211307_S_AT, 239519_AT, 209835_X_AT, 218856_AT,21

686_S_AT, 229937_X_AT, 207700_S_AT, 203104_AT, 212977_AT, 223939_AT,203887_S_AT, 228766_AT, 203508_AT, 210845_S_AT, 241773_AT, 209392_AT,233220_AT, 204774_AT, 214581_X_AT, 237252_AT, 216248_S_AT, 204622_X_AT,210233_AT, 214866_AT, 226218_AT, 205099_S_AT, 211661_X_AT, 1557905_S_AT,2026

6_S_AT, 222062_AT, 209670_AT, 235944_AT, 238542_AT, 217552_X_AT,217078_S_AT, 205419_AT, 202071_AT, 210839_S_AT, 209906_AT, 221840_AT,202068_S_AT, 211676_S_AT, 208121_S_AT, 220313_AT, 205718_AT, 203888_AT,203935_AT, 203233_AT, 210173_AT, 241929_AT, 201125_S_AT, 202067_S_AT,219434_AT, 2050

8_AT GOTERM_(—) 229221_AT, 21229

_AT, 209555_S_AT, 216243_S_AT, 212014_X_AT, 216834_AT, 210916_S_AT,MF_ALL 211352_S_AT, 235739_AT, 207674_AT, 242871_AT, 236561_AT,217173_S_AT, 2044

_S_AT, 203760_S_AT, 207610_S_AT, 220307_AT, 211307_S_AT, 229937_X_AT,218686_S_AT, 207700_S_AT, 20

104_AT, 212977_AT, 228766_AT, 203508_AT, 210845_S_AT, 233220_AT,237252_AT, 214581_X_AT, 214297_AT, 216248_S_AT, 220233_AT, 1405_I_AT,214866_AT, 205099_S_AT, 1557905_S_AT, 235

44_AT, 238542_AT, 209670_AT, 217078_S_AT, 209906_AT, 221

40_AT, 20

121_S_AT, 211676_S_AT, 203233_AT, 217591_AT, 201125_S_AT, 204912_AT,37152_AT, 211924_S_AT, 222877_AT, 212657_S_AT, 2064

_S_AT, 206171_AT, 200878_AT, 202388_AT, 204736_S_AT, 205891_AT,203665_AT, 204359_AT, 204490_S_AT, 239519_AT, 20

35_X_AT, 218856_AT, 203887_S_AT, 223939_AT, 202988_S_AT, 209392_AT,241773_AT, 204774_AT, 204622_X_AT, 214724_AT, 226218_AT, 211661_X_AT,222062_AT, 2026

6_S_AT, 225207_AT, 217552_AT, 205419_AT, 202071_AT, 210839_S_AT,204655_AT, 202068_S_AT, 214054_AT, 220313_AT, 205718_AT, 201

88_AT, 203935_AT, 203761_AT, 210258_AT, 1555759_A_AT, 210173_AT,241929_AT, 21

34_AT, 202067_S_AT, 203320_AT, 2050

_AT GOTERM_(—) 229221_AT, 212298_AT, 209555_S_AT, 216243_S_AT,212014_X_AT, 216834_AT, 210916_S_AT, MF_ALL 211352_S_AT, 23573

_AT, 207574_AT, 242871_AT, 232563_AT, 217173_S_AT, 2044

9_S_AT, 203760_S_AT, 207610_S_AT, 220307_AT, 211307_S_AT, 229937_X_AT,21

6_S_AT, 207700_S_AT, 203104_AT, 212977_AT, 228766_AT, 20

50

_AT, 210845_S_AT, 233220_AT, 237252_AT, 214581_X_AT, 214297_AT,216248_S_AT, 210233_AT, 1405_I_AT, 214

6_AT, 205099_S_AT 1557905_S_AT, 235944_AT, 23

542_AT, 209670_AT, 217078_AT, 209906_AT, 221

40_AT, 2

121_S_AT, 211676_S_AT, 203233_AT, 2175

1_AT, 201125_S_AT, 204912_AT, 37152_AT, 211924_S_AT, 222877_AT,212657_S_AT, 2064

_S_AT, 206171_AT, 200

7

_AT, 202388_AT, 204736_S_AT, 20

1_AT, 203665_AT, 204359_AT, 204490_S_AT, 239519_AT, 209835_X_AT,218856_AT, 203

7_S_AT, 223939_AT, 20298

_S_AT, 209392_AT, 241773_AT, 204774_AT, 204622_X_AT, 214724_AT,226214_AT, 211661_X_AT, 222062_AT, 202686_S_AT, 225207_AT, 217552_X_AT,205419_AT, 202071_AT, 210

39_S_AT, 204655_AT, 202068_S_AT, 214054_AT, 220313_AT, 20571

_AT, 203888_AT, 203935_AT, 20

761_AT, 210258_AT, 155575

_A_AT, 210173_AT, 241

29_AT, 219434_AT, 202067_S_AT, 203320_AT, 20509

_AT GOTERM_(—) 237252_AT, 204912_AT, 21229

_AT, 20

555_S_AT, 210233_AT, 222877_AT, 22621

_AT, MF_ALL 205099_S_AT, 211661_X_AT, 206488_S_AT, 222062_AT,202686_S_AT, 206171_AT, 238542_AT, 235944_AT, 236561_AT, 217552_X_AT,205419_AT, 210

39_S_AT, 217173_S_AT, 20

906_AT, 205

1_AT, 207610_S_AT, 221840_AT, 239519_AT, 202068_S_AT, 20

121_S_AT, 211676_S_AT, 220313_AT, 203888_AT, 203935_AT, 203104_AT,203233_AT, 212977_AT, 203887_S_AT, 223939_AT, 228766_AT, 203508_AT, 20

92_AT, 24192

_AT, 241773_AT, 210173_AT, 202067_S_AT, 233220_AT, 204774_AT, 2050

8_AT GOTERM_(—) 201464_X_AT, 160020_AT, 201465_S_AT, 229221_AT,201069_AT, 212171_X_AT, 213503_X_AT, BP_ALL 21229

_AT, 214297_AT, 39402_AT, 205463_S_AT, 212014_X_AT, 210427_X_AT,201473_AT, 222

77_AT, 210916_S_AT, 24193

_AT, 22

30_AT, 1557905_S_AT, 211962_S_AT, 202

2

_S_AT, 205067_AT, 210512_S_AT, 202827_S_AT, 202

59_X_AT, 236561_AT, 211527_X_AT, 200

78_AT, 204489_S_AT, 20

5_AT, 204736_S_AT, 204490_S_AT, 2132

1_AT, 212099_AT, 208816_X_AT, 310513_S_AT, 239519_AT, 209

35_X_AT, 201590_X_AT, 201466_S_AT, 203955_AT, 204035_AT, 212124_AT, 20

37_S_AT, 210173_AT, 2172

_X_AT GOTERM_(—) 229221_AT, 223723_AT, 210495_X_AT, 210136_AT,209555_S_AT, 212014_X_AT, 203923_S_AT, CC_ALL 210915_S_AT, 219412_AT,207674_AT, 202828_S_AT, 236561_AT, 201925_S_AT, 217173_S_AT,204489_S_AT, 220

07_AT, 211307_S_AT, 223303_AT, 203922_S_AT, 214

30_AT, 1552914_A_AT, 203304_AT, 202756_S_AT, 228766_AT, 230

25_AT, 201005_AT, 206033_S_AT, 201242_S_AT, 233220_AT, 242907_AT,207819_S_AT, 237252_AT, 160020_AT, 214297_AT, 210233_AT, 228910_AT,209949_AT, 211719_X_AT, 34210_AT, 205534_AT, 2050

_S_AT, 20

94_S_AT, 1557905_S_AT, 22

754_AT, 23

542_AT, 209670_AT, 209047_AT, 238581_AT, 209906_AT, 211030_S_AT,205520_AT, 20

121_S_AT, 211676_S_AT, 2352

5_AT, 204105_S_AT, 20

233_AT, 219994_AT, 201125_S_AT, 217279_X_AT, 201243_S_AT, 203217_S_AT,2064

_S_AT, 206171_AT, 22

640_AT, 205542_AT, 204736_S_AT, 205891_AT, 203665_AT, 20435

_AT, 204490_S_AT, 202748_AT, 209835_X_AT, 20

161_S_AT, 204715_AT, 203887_S_AT, 209392_AT, 241773_AT, 224859_AT,209999_AT, 201012_AT, 212464_S_AT, 216442_X_AT, 214724_AT, 226218_AT,204661_AT, 227107_AT, 204401_AT, 211661_X_AT, 222062_AT, 202686_S_AT,217552_X_AT, 225188_AT, 2230

2_AT, 202

27_S_AT, 205419_AT, 202071_AT, 210839_S_AT, 219332_AT, 20206

_S_AT, 20671

_AT, 203888_AT, 203935_AT, 15565

3_A_AT, 22

302_AT, 241929_AT, 210173_AT, 202067_S_AT, 205098_AT GOTERM_(—)201464_X_AT, 202540_S_AT, 227069_AT, 229221_AT, 201465_S_AT, 210136_AT,21229

_AT, BP_ALL 212014_X_AT, 221731_X_AT, 201473_AT, 210

16_S_AT, 235739_AT, 206472_S_AT, 20

960_S_AT, 202828_S_AT, 205067_AT, 209

03_S_AT, 23

561_AT, 230360_AT, 202

59_X_AT, 2022

4_S_AT, 1569149_AT, 2044

9_S_AT, 216017_S_AT, 204620_S_AT, 2120

9_AT, 201147_S_AT, 201565_S_AT, 201590_X_AT, 232649_AT, 204653_AT,1555832_S_AT, 210

45_S_AT, 243556_AT, 201005_AT, 20

61_S_AT, 233220_AT, 210095_S_AT, 160020_AT, 234967_AT, 216248_S_AT,214297_AT, 212171_X_AT, 39402_AT, 205463_S_AT, 201566_X_AT, 214866_AT,22

964_AT, 202191_S_AT, 229

30_AT, 1557905_S_AT, 21

502_S_AT, 20

35_AT, 222670_S_AT, 201150_S_AT, 203751_X_AT, 20114

_S_AT, 1554992_AT, 213283_AT, 224606_AT, 204619_S_AT, 215646_S_AT,210513_S_AT, 1554600_S_AT, 204105_S_AT, 204

1_S_AT, 203752_S_AT, 212

03_AT, 225557_AT, 217279_X_AT, 37152_AT, 20106

_AT, 221

41_S_AT, 211924_S_AT, 22421

_S_AT, 222

77_AT, 241938_AT, 211962_S_AT, 15

6901_AT, 200

78_AT, 204141_AT, 204736_S_AT, 203665_AT, 2044

0_S_AT, 204998_S_AT, 20

816_X_AT, 201149_S_AT, 23

519_AT, 209835_X_AT, 212190_AT, 201466_S_AT, 212143_S_AT, 204035_AT,212086_X_AT, 220484_AT, 212124_AT, 20

37_S_AT, 22

762_AT, 222651_S_AT, 2119

6_AT, 230529_AT, 201324_AT, 201012_AT, 202539_S_AT, 213503_X_AT,204622_X_AT, 227240_AT, 210427_X_AT, 226218_AT, 21

559_S_AT, 202686_S_AT, 204

4_AT, 219845_AT, 210512_S_AT, 223092_AT, 202

27_S_AT, 205419_AT, 211527_X_AT, 1562467_AT, 2

4465_S_AT, 203140_AT, 220266_S_AT, 220935_S_AT, 2091

9_AT, 212372_AT, 203935_AT, 2120

9_AT, 2019

5_AT, 227697_AT, 229797_AT, 203411_S_AT, 210173_AT, 211571_S_AT, 2156

_AT, 203320_AT GOTERM_(—) 201464_X_AT, 160020_AT, 2014

5_S_AT, 214297_AT, 21229

_AT, 213503_X_AT, 212171_X_AT, BP_ALL 39402_AT, 205463_S_AT,210427_X_AT, 201473_AT, 222877_AT, 24193

_AT, 229

30_AT, 211962_S_AT, 202828_S_AT, 205067_AT, 210512_S_AT, 202

5

_X_AT, 202

27_S_AT, 236561_AT, 211527_X_AT, 200

78_AT, 20366

_AT, 204736_S_AT, 2132

1_AT, 2120

9_AT, 20

816_X_AT, 23

519_AT, 210513_S_AT, 201590_X_AT, 201466_S_AT, 203935_AT, 204035_AT,212124_AT, 20

37_S_AT, 210173_AT, 21727

_X_AT GOTERM_(—) 201464_X_AT, 160020_AT, 201465_S_AT, 229221_AT,201069_AT, 212171_X_AT, 213503_X_AT, BP_ALL 212298_AT, 214297_AT,39402_AT, 205463_S_AT, 212014_X_AT, 210427_X_AT, 201473_AT 222

77_AT, 210916_S_AT, 241938_AT, 229

30_AT, 1557905_S_AT, 211962_S_AT, 202828_S_AT, 205067_AT, 210512_S_AT,202827_S_AT, 20285

_X_AT, 236561_AT, 211527_X_AT, 200

7

_AT, 204489_S_AT, 203665_AT, 204736_S_AT, 204490_S_AT, 213281_AT,212099_AT, 208816_X_AT 210513_S_AT, 239519_AT, 209635_X_AT, 201590_X_AT,201466_S_AT, 203935_AT, 204035_AT, 212124_AT, 208937_S_AT, 210173_AT,217279_X_AT GOTERM_(—) 201464_X_AT, 210495_X_AT, 229221_AT, 201465_S_AT,219028_AT, 21229

_AT, 209555_S_AT, BP_ALL 216243_S_AT, 212014_X_AT, 221731_X_AT,203923_S_AT, 203074_AT, 210916_S_AT, 201471_S_AT 235739_AT, 20

960_S_AT, 202

28_S_AT, 205067_AT, 236561_AT, 202859_X_AT, 202284_S_AT, 201925_S_AT,228490_AT, 204489_S_AT, 204620_S_AT, 201147_S_AT, 203922_S_AT, 221

15_AT, 225115_AT, 1555832_S_AT, 228766_AT, 205495_S_AT, 203508_AT, 210

45_S_AT, 201005_AT, 208961_S_AT, 201242_S_AT, 20

43

_S_AT, 237252_AT, 160020_AT, 212171_X_AT, 21624

_S_AT, 63825_AT, 39402_AT, 205463_S_AT, 210233_AT, 1405_I_AT, 214866_AT,211719_X_AT, 209949_AT, 229

30_AT, 202086_AT, 20509

_S_AT, 205566_AT, 1557

05_S_AT, 23

18_X_AT, 209670_AT, 235944_AT, 221463_AT, 20

436_S_AT, 201150_S_AT, 20114

_S_AT, 20

06_AT, 201739_AT, 217757_AT, 213281_AT, 224606_AT, 204619_S_AT,215646_S_AT, 20162

_AT, 210513_S_AT, 23866

_AT, 239452_AT, 37028_AT, 2250

7_AT, 217279_X_AT, 201627_S_AT, 201243_S_AT, 37152_AT, 201069_AT, 22794

_AT, 211924_S_AT, 202708_S_AT, 212948_AT, 201041_S_AT, 212657_S_AT, 2064

_S_AT, 213763_AT, 206171_AT, 220066_AT, 200878_AT, 202014_AT, 205891_AT,203665_AT, 204490_S_AT, 201149_S_AT, 239519_AT, 209835_X_AT, 225116_AT,206157_AT, 201466_S_AT, 225337_AT, 204035_AT, 203887_S_AT, 225368_AT,201625_S_AT, 201012_AT, 212464_S_AT, 216442_X_AT, 204622_X_AT, 21

34_S_AT, 204401_AT, 211661_X_AT, 222062_AT, 217552_X_AT, 210512_S_AT,202827_S_AT,

7100_AT, 211527_X_AT, 15624

7_AT, 204465_S_AT, 206573_S_AT, 203140_AT, 202241_AT, 204655_AT,1552553_A_AT, 2091

9_AT, 201044_X_AT, 203

_AT, 212372_AT, 203935_AT, 1556583_A_AT, 227

7_AT, 1555759_A_AT, 141929_AT, 211571_AT, 20509

_AT GOTERM_(—) 210136_AT, 205552_S_AT, 216243_S_AT, 204972_AT, 216

34_AT, 203923_S_AT, 201471_S_AT, BP_ALL 207674_AT, 212657_S_AT,205067_AT, 202859_X_AT, 220066_AT, 209827_S_AT, 201925_S_AT, 20274

_AT, 211307_S_AT, 203922_S_AT, 229937_X_AT, 223502_S_AT, 206157_AT,1552914_A_AT, 20

50

_AT, 2029

_S_AT, 209392_AT, 224859_AT, 242907_AT, 213293_S_AT, 214211_AT,212171_X_AT, 39402_AT, 210233_AT, 1405_I_AT, 209949_AT, 22621

_AT, 223501_AT, 2050

9_S_AT, 200748_S_AT, 211661_X_AT, 222062_AT, 238542_AT, 217552_X_AT,210512_S_AT, 217078_S_AT, 221463_AT, 205419_AT, 211527_X_AT, 238581_AT,210

39_S_AT, 204655_AT, 210513_S_AT, 203233_AT, 1555759_A_AT, 219434_AT,205098_AT GOTERM_(—) 210495_X_AT, 229221_AT, 216243_S_AT, 212014_X_AT,203923_S_AT, 202708_S_AT, 210916_S_AT, BP_ALL 212

57_S_AT, 206171_AT, 205067_AT, 202859_X_AT, 220066_AT, 201925_S_AT,204489_S_AT, 205891_AT, 203

65_AT, 204490_S_AT, 209835_X_AT, 20

922_S_AT, 206157_AT, 204035_AT, 205495_S_AT, 20350

_AT, 201012_AT, 20

438_S_AT, 212464_S_AT, 216442_X_AT, 39402_AT, 210233_AT, 1405_I_AT,21171

_X_AT, 200949_AT, 2020

_AT, 205099_S_AT, 211

61_X_AT, 204401_AT, 1557905_S_AT, 22

062_AT, 20

670_AT, 217552_X_AT, 221463_AT, 208436_S_AT, 209506_AT, 217757_AT, 204

55_AT, 209189_AT, 1552553_A_AT, 203935_AT, 1555759_A_AT, 2050

_AT GOTERM_(—) 202540_S_AT, 201464_X_AT, 201465_S_AT, 229221_AT,227069_AT, 219028_AT, 210136_AT, BP_ALL 212298_AT, 209555_S_AT,202435_S_AT, 212014_X_AT, 221731_X_AT, 221011_S_AT, 201473_AT,203074_AT, 210916_S_AT, 235739_AT, 206472_S_AT, 20

960_S_AT, 203882_AT, 202828_S_AT, 205067_AT, 242871_AT, 209803_S_AT,202284_S_AT, 202859_X_AT, 230360_AT, 236561_AT, 1569149_AT, 217173_S_AT,204489_S_AT, 216017_S_AT, 204620_S_AT, 212099_AT, 201565_S_AT,201147_S_AT, 201590_X_AT, 232649_AT, 204653_AT, 203104_AT, 225115_AT,1555832_S_AT, 22

766_AT, 210845_S_AT, 243556_AT, 201005_AT, 208961_S_AT, 233220_AT,210095_S_AT, 237252_AT, 160020_AT, 214297_AT, 212171_X_AT, 216248_S_AT,224967_AT, 39402_AT, 205463_S_AT, 201566_X_ATT, 22

64_AT, 214866_AT, 202191_S_AT, 229830_AT, 1552690_A_AT, 1557905_S_AT,206

35_AT, 21

502_S_AT, 235944_AT, 222670_S_AT, 209047_AT, 203751_X_AT, 201150_S_AT,201148_S_AT, 1554992_AT, 209906_AT, 202768_AT, 213281_AT, 224606_AT,204619_AT, 215646_S_AT, 210513_S_AT, 1554600_S_AT, 238669_AT,204105_S_AT, 204881_S_AT, 225097_AT, 203752_S_AT, 212803_AT, 225557_AT,217591_AT, 217279_X_AT, 37152_AT, 201069_AT, 221842_S_AT, 221924_S_AT,224218_S_AT, 222877_AT, 241938_AT, 212948_AT, 228083_AT, 202434_S_AT,206488_S_AT, 213763_AT, 211962_S_AT, 1566901_AT, 220066_AT, 200878_AT,204141_AT, 202388_AT, 205891_AT, 204736_S_AT, 203665_AT, 202436_S_AT,204490_S_AT, 2049

_S_AT, 208816_X_AT, 201149_S_AT, 239519_AT, 209835_X_AT, 225116_AT,212190_AT, 201466_S_AT, 212143_S_AT, 204033_AT, 212086_X_AT, 220484_AT,203887_S_AT, 212124_AT, 225368_AT, 208937_S_AT, 228762_AT, 222651_S_AT,230529_AT, 211986_AT, 201324_AT, 202539_S_AT, 201012_AT, 213503_X_AT,204622_X_AT, 227240_AT, 241722_X_AT, 210427_X_AT, 214724_AT, 226218_AT,228559_S_AT, 204401_AT, 211661_X_AT, 2026

6_S_AT, 2046

4_AT, 219

45_AT, 21990

_AT, 223092_AT, 210512_S_AT, 202827_S_AT, 205419_AT, 211527_X_AT,204475_AT, 1562467_AT, 204465_S_AT, 203140_AT, 220266_S_AT, 220935_S_AT,1552553_A_AT, 202437_S_AT, 209189_AT, 202068_S_AT, 203

88_AT, 212372_AT, 203935_AT, 2120

9_AT, 227697_AT, 201995_AT, 15565

3_A_AT, 229797_AT, 203411_S_AT, 210173_AT, 241929_AT, 202067_S_AT,211571_S_AT, 215688_AT, 203320_AT GOTERM_(—) 229221_AT, 216442_X_AT,210435_X_AT, 39402_AT, 210233_AT, 216243_S_AT, 1405_I_AT, BP_ALL212014_X_AT, 211719_X_AT, 230

23_S_AT, 210916_S_AT, 205099_S_AT, 211661_X_AT, 212657_S_AT,1557905_S_AT, 206171_AT, 205067_AT, 217552_X_AT, 202859_X_AT, 20

436_S_AT, 221463_AT, 201925_S_AT, 20

06_AT, 2044

_S_AT, 203665_AT, 204490_S_AT, 217757_AT, 204655_AT, 1552553_A_AT, 2091

9_AT, 209

35_X_AT, 203922_S_AT, 205157_AT, 204035_AT, 203935_AT, 203508_AT,1555759_A_AT, 201012_AT, 2050

_AT, 2124

4_S_AT GOTERM_(—) 201464_X_AT, 202540_S_AT, 22706

_AT, 229221_AT, 201465_S_AT, 21902

_AT, 210136_AT, BP_ALL 21225

_AT, 212014_X_AT, 221731_X_AT, 201473_AT, 221011_S_AT, 210916_S_AT,235739_AT, 206472_S_AT, 20

960_S_AT, 202

28_S_AT, 209

0

_S_AT, 242

71_AT, 205067_AT, 2022

4_S_AT, 236561_AT, 230360_AT, 202859_X_AT, 1569149_AT, 20

_S_AT, 216017_S_AT, 204620_S_AT, 212099_AT, 201147_S_AT, 201565_S_AT,201590_X_AT, 232

49_AT, 204653_AT, 203104_AT, 225115_AT, 1555

32_S_AT, 210845_S_AT, 243556_AT, 201005_AT, 208961_S_AT, 233220_AT,210095_S_AT, 237252_AT, 160020_AT, 224967_AT, 216248_S_AT, 234297_AT,212171_X_AT, 39402_AT, 2054

3_S_AT, 201566_X_AT, 214

66_AT, 22

964_AT, 202191_S_AT, 229

30_AT, 1557905_S_AT, 21

502_S_AT, 206

35_AT, 222670_S_AT, 201150_S_AT, 20

751_X_AT, 20114

_S_AT, 1554992_AT, 202768_AT, 2132

1_AT, 224606_AT, 204619_S_AT, 2156

6_S_AT, 210513_S_AT, 1554600_S_AT, 204105_S_AT, 204

1_S_AT, 225097_AT, 20

752_S_AT, 212

03_AT, 225557_AT, 217279_X_AT, 217591_AT, 37152_AT, 201069_AT,221841_S_AT, 211924_S_AT, 224218_S_AT, 222877_AT, 24193

_AT, 213763_AT, 211962_S_AT, 1566901_AT, 200

_AT, 204141_AT, 204736_S_AT, 203665_AT, 204490_S_AT, 204998_S_AT,208816_X_AT, 201149_S_AT, 239519_AT, 209

35_X_AT, 225116_AT, 232150_AT, 201466_S_AT, 212143_S_AT, 204035_AT, 2120

6_X_AT, 2204

4_AT, 203

7_S_AT, 212134_AT, 225368_AT, 208937_S_AT, 228762_AT, 222651_S_AT, 2219

_AT, 230529_AT, 201324_AT, 201012_AT, 202539_S_AT, 213503_X_AT,204622_X_AT, 227240_AT, 241722_X_AT, 210427_X_AT, 214724_AT, 22621

_AT, 218559_S_AT, 2026

6_S_AT, 204684_AT, 219

45_AT, 219906_AT, 202

27_S_AT, 210512_S_AT, 223092_AT, 205419_AT, 211527_X_AT, 1562467_AT,204465_S_AT, 203140_AT, 220266_S_AT, 220935_S_AT, 209189_AT, 212372_AT,203

_AT, 203935_AT, 2120

9_AT, 201996_AT, 227697_AT, 229797_AT, 203411_S_AT, 210173_AT,211571_S_AT, 2136

_AT, 203320_AT GOTERM_(—) 202540_S_AT, 210495_X_AT, 229221_AT, 37152_AT,212298_AT, 212014_X_AT, 211924_S_AT, BP_ALL 221732_X_AT, 222877_AT,210915_S_AT, 204268_AT, 235735_AT, 223220_S_AT, 202

2

_S_AT, 205067_AT, 202859_X_AT, 236561_AT, 209

27_S_AT, 204489_S_AT, 204490_S_AT, 204620_S_AT, 239519_AT, 209835_X_AT,204035_AT, 208937_S_AT, 209392_AT, 210

45_S_AT, 202539_S_AT, 212464_S_AT, 160020_AT, 216442_X_AT, 216248_S_AT,39402_AT, 204622_X_AT, 2054

3_S_AT, 1405_I_AT, 214

66_AT, 211719_X_AT, 229

30_AT, 205099_S_AT, 211661_X_AT, 1557935_S_AT, 200921_S_AT, 202827_S_AT,221463_AT, 200920_S_AT, 210839_S_AT, 209906_AT, 204655_AT, 21564

_S_AT, 204619_S_AT, 212372_AT, 20

35_AT, 204105_S_AT, 1555759_A_AT, 217279_X_AT, 211571_S_AT, 205098_ATGOTERM_(—) 202540_S_AT, 201464_X_AT, 210495_X_AT, 201465_S_AT,229221_AT, 227069_AT, 219028_AT, BP_ALL 210136_AT, 212298_AT,212014_X_AT, 221731_X_AT, 221011_S_AT, 201473_AT, 210916_S_AT,201471_S_AT, 235739_AT, 206472_S_AT, 208960_S_AT, 202828_S_AT,205067_AT, 242871_AT, 209

03_S_AT, 226648_AT, 2022

4_S_AT, 202

59_X_AT, 230360_AT, 236561_AT, 156

149_AT, 204489_S_AT, 216017_S_AT, 208891_AT, 204620_S_AT, 212099_AT,201565_S_AT, 201147_S_AT, 201590_X_AT, 232649_AT, 204653_AT, 203104_AT,225115_AT, 1555

32_S_AT, 210845_S_AT, 243556_AT, 201005_AT, 20

961_S_AT, 233220_AT, 210095_S_AT, 237252_AT, 160020_AT, 214297_AT,212171_X_AT, 216248_S_AT, 224967_AT, 39402_AT, 205463_S_AT, 1405_I_AT,201566_X_AT, 22

964_AT, 211719_X_AT, 214

66_AT, 202191_AT, 229

30_AT, 1557905_S_AT, 21

502_S_AT, 206835_AT, 222670_S_AT, 203751_X_AT, 201150_S_AT, 201148_S_AT,155

992_AT, 202768_AT, 2132

1_AT, 224606_AT, 204619_S_AT, 215646_S_AT, 210613_S_AT, 1554600_S_AT, 23

669_AT, 204105_S_AT, 204

1_S_AT, 225097_AT, 20

752_S_AT, 212803_AT, 225557_AT, 217591_AT, 217279_X_AT, 37152_AT,201069_AT, 221841_S_AT, 211924_S_AT, 224218_S_AT, 222

77_AT, 24193

_AT, 213763_AT, 211962_S_AT, 1566001_AT, 200

78_AT, 204141_AT, 202388_AT, 20

736_S_AT, 203665_AT, 204490_S_AT, 20499

_S_AT, 20

16_X_AT, 201149_S_AT, 23

19_AT, 209835_X_AT, 225116_AT, 212190_AT, 201466_S_AT, 212143_S_AT,204035_AT, 2120

_X_AT, 220484_AT, 203887_S_AT, 212124_AT, 225368_AT, 208537_S_AT,228762_AT, 222651_S_AT, 230529_AT, 211986_AT, 201324_AT, 202539_S_AT,301012_AT, 212464_S_AT, 216442_X_AT, 213503_X_AT, 204622_X_AT,227240_AT, 241722_X_AT, 210427_X_AT, 214724_AT, 226218_AT, 218559_S_AT,202686_S_AT, 204684_AT, 20

_S_AT, 219

45_AT, 21990

_AT, 223092_AT, 210512_S_AT, 202827_S_AT, 205419_AT, 211527_X_AT,1562467_AT, 204465_S_AT, 203140_AT, 20

92_S_AT, 220266_S_AT, 220935_S_AT, 204655_AT, 2091

9_AT, 203

_AT, 212372_AT, 203935_AT, 212089_AT, 227637_AT, 201995_AT, 229797_AT,1555759_A_AT, 203411_S_AT, 210173_AT, 211571_S_AT, 2156

8_AT, 203320_AT GOTERM_(—) 160020_AT, 3

402_AT, 2054

3_S_AT, 216243_S_AT, 1405_I_AT, 201473_AT, 229

30_AT, BP_ALL 201041_S_AT, 212657_S_AT, 202

28_S_AT, 205067_AT, 2022

4_S_AT, 202827_S_AT, 236561_AT, 209047_AT, 201150_S_AT, 217173_S_AT,201148_S_AT, 203665_AT, 217757_AT, 204655_AT, 201149_S_AT, 2091

_AT, 201147_S_AT, 202068_S_AT, 201044_X_AT, 23

669_AT, 201313_AT, 227697_AT, 1555759_A_AT, 217279_X_AT, 202067_S_AT,207819_S_AT GOTERM_(—) 237252_AT, 216442_X_AT, 210495_X_AT, 201069_AT,212171_X_AT, 39402_AT, 205463_S_AT, CC_ALL 216243_S_AT, 1405_I_AT,211719_X_AT, 223501_AT, 229830_AT, 212657_S_AT, 203940_S_AT, 227265_AT,23

542_AT, 203548_S_AT, 205067_AT, 219908_AT, 210512_S_AT, 202

59_X_AT, 221463_AT, 226545_AT, 211527_X_AT, 209827_S_AT, 217273_S_AT,203665_AT, 217757_AT, 204655_AT, 210513_S_AT, 202068_S_AT, 21219_AT,223502_S_AT, 203

8_AT, 212143_S_AT, 204035_AT, 203887_S_AT, 202756_S_AT, 204

34_AT, 205495_S_AT, 1555759_A_AT, 216546_S_AT, 202067_S_AT, 210095_S_AT,212464_S_AT GOTERM_(—) 201464_X_AT, 202540_S_AT, 210495_X_AT, 227069_AT,229221_AT, 201465_S_AT, 210136_AT, BP_ALL 212298_AT, 212014_X_AT,221731_X_AT, 201473_AT, 210916_S_AT, 235739_AT, 206472_S_AT, 20

960_S_AT, 202

2

_S_AT, 205067_AT, 209

03_S_AT, 236561_AT, 230360_AT, 202859_X_AT, 202284_S_AT, 156

149_AT, 204489_S_AT, 21

017_S_AT, 204620_S_AT, 212099_AT, 201147_S_AT, 201565_S_AT, 201590_X_AT,232649_AT, 204653_AT, 1555832_S_AT, 210845_S_AT, 243

6_AT, 201005_AT, 208961_S_AT, 233220_AT, 2100

5_S_AT, 250020_AT, 224967_AT, 21624

_S_AT, 214297_AT, 212171_X_AT, 39402_AT, 205463_S_AT, 201566_X_AT,214866_AT, 228964_AT, 211719_X_AT, 202191_S_AT, 229830_AT, 1557905_S_AT,21

502_S_AT, 206835_AT, 222670_S_AT, 201150_S_AT, 203751_X_AT, 20114

_S_AT, 1554992_AT, 2132

1_AT, 224

06_AT, 20461

_S_AT, 215646_S_AT, 210513_S_AT, 1554600_S_AT, 204105_S_AT, 204

1_S_AT, 203752_S_AT, 212

03_AT, 225557_AT, 217279_X_AT, 37152_AT, 201069_AT, 221

41_S_AT, 211924_S_AT, 224218_S_AT, 222877_AT, 241938_AT, 211962_AT,1566901_AT, 200

7

_AT, 204141_AT, 204736_S_AT, 203665_AT, 204490_S_AT, 204998_S_AT, 20

16_X_AT, 20114

_S_AT, 239519_AT,

09

35_X_AT, 212190_AT, 201466_S_AT, 212143_S_AT, 204035_AT, 2120

6_X_AT, 220484_AT, 212124_AT, 20

37_S_AT, 22

762_AT, 222651_S_AT, 211986_AT, 230529_AT, 201324_AT, 201012_AT,202539_S_AT, 212464_S_AT, 216442_X_AT, 213503_X_AT, 204622_X_AT,227240_AT, 210427_X_AT 226218_AT, 218559_S_AT, 2026

6_S_AT, 2046

4_AT, 2198

5_AT, 210512_S_AT, 223092_AT, 202

27_S_AT, 205419_AT, 211527_X_AT, 1562467_AT, 204465_S_AT, 203140_AT,220266_S_AT, 220935_S_AT, 209189_AT, 212372_AT, 203935_AT, 2120

_AT, 201995_AT, 2276

7_AT, 229797_AT, 203411_S_AT, 210173_AT, 212571_S_AT, 2156

_AT, 203

0_AT GOTERM_(—) 21902

_AT, 212171_X_AT, 213503_X_AT, 39402_AT, 205463_S_AT, 227948_AT,1405_I_AT, BP_ALL 210427_X_AT, 226218_AT, 223501_AT, 229830_AT,204923_AT, 213763_AT, 222062_AT, 205067_AT, 210512_S_AT, 202

59_X_AT, 217552_X_AT, 208436_S_AT, 220066_AT, 211527_X_AT, 209827_S_AT,203939_AT, 201925_S_AT, 209906_AT, 203665_AT, 205

91_AT, 20

140_AT, 217757_AT, 20

16_X_AT, 204655_AT, 210513_S_AT, 201590_X_AT, 225116_AT, 223502_S_AT,1552914_A_AT, 204035_AT, 225115_AT, 203233_AT, 2276

7_AT, 225097_AT, 203508_AT, 225368_AT, 155575

_A_AT, 224859_AT, 233220_AT GOTERM_(—) 210136_AT, 205552_S_AT,204972_AT, 216243_S_AT, 216834_AT, 203923_S_AT, 201471_S_AT, BP_ALL207674_AT, 212657_S_AT, 20

960_S_AT, 205067_AT, 202859_X_AT, 236561_AT, 220066_AT, 209827_S_AT, 200

78_AT, 201925_S_AT, 202748_AT, 211307_S_AT, 201565_S_AT, 203922_S_AT,229937_X_AT, 223502_S_AT, 206157_AT, 1552914_A_AT, 204035_AT,1555832_S_AT, 203508_AT, 2029

_S_AT, 209392_AT, 224859_AT, 208961_S_AT, 242907_AT, 213293_S_AT,214211_AT, 212171_X_AT, 39402_AT, 210233_AT, 1405_I_AT, 201566_X_AT,209949_AT, 226218_AT, 223501_AT, 200748_S_AT, 205099_S_AT, 211661_X_AT,22262_AT, 219

45_AT, 23

542_AT, 210512_S_AT, 217552_X_AT, 221453_AT, 217078_S_AT, 205419_AT,211527_X_AT, 23

581_AT, 210839_S_AT, 209906_AT, 203140_AT, 224606_AT, 204655_AT,210513_S_AT, 203233_AT, 1555759_A_AT, 219434_AT, 203320_AT, 2050

_AT GOTERM_(—) 160020_AT, 210495_X_AT, 216442_X_AT, 229221_AT,201069_AT, 212171_X_AT, 213503_X_AT, CC_ALL 212014_X_AT, 210427_X_AT,21719_X_AT, 221731_X_AT, 210916_S_AT, 1557905_S_AT, 202828_S_AT,215944_AT, 203548_S_AT, 210512_S_AT, 202827_S_AT, 211527_X_AT,204475_AT, 201150_S_AT, 20114

_S_AT, 204489_S_AT, 213428_S_AT, 204358_AT, 204490_S_AT, 208816_X_AT,204620_S_AT, 229004_AT, 201149_S_AT, 210513_S_AT, 201147_S_AT,215646_S_AT, 204619_S_AT, 209835_X_AT, 201590_X_AT, 202756_S_AT, 22

73_AT, 226546_S_AT, 217279_X_AT, 211571_S_AT, 212

4_S_AT GOTERM_(—) 160020_AT, 201464_X_AT, 201465_S_AT, 214297_AT,212298_AT, 213503_X_AT, 212171_X_AT, BP_ALL 39402_AT, 205463_S_AT,210427_X_AT, 222877_AT, 229830_AT, 202828_S_AT, 205067_AT, 202827_S_AT,202859_X_AT, 210512_S_AT, 211527_X_AT, 200

78_AT, 203665_AT, 204736_S_AT, 2132

1_AT, 212099_AT, 208816_X_AT, 239519_AT, 210513_S_AT, 201590_X_AT, 2014

6_S_AT, 20

35_AT, 204035_AT, 20

37_S_AT, 217279_X_AT GOTERM_(—) 201464_X_AT, 237252_AT, 201465_S_AT,39402_AT, 1405_I_AT, 20270

_S_AT, 202086_AT, BP_ALL 211661_X_AT, 222062_AT, 203882_AT, 239818_X_AT,205067_AT, 220066_AT, 208436_S_AT, 214453_S_AT, 202241_AT, 213281_AT,204655_AT, 209189_AT, 1552553_A_AT, 211676_S_AT, 229937_X_AT,201466_S_AT, 206157_AT, 203

_AT, 227697_AT, 203

7_S_AT, 205495_S_AT, 1555759_A_AT, 20843

_S_AT, 213293_S_AT GOTERM_(—) 202540_S_AT, 160020_AT, 229221_AT,210495_X_AT, 216442_X_AT, 37152_AT, 212298_AT, BP_ALL 21624

_S_AT, 39402_AT, 204622_X_AT, 1405_I_AT, 212014_X_AT, 221731_X_AT,211719_X_AT, 222

77_AT, 210916_S_AT, 204268_AT, 235739_AT, 223220_S_AT, 1557905_S_AT,200921_S_AT, 202

28_S_AT, 205067_AT, 202

59_X_AT, 202827_S_AT, 236561_AT, 200920_S_AT, 209827_S_AT 2044

_S_AT, 204490_S_AT, 204620_S_AT, 204655_AT, 239519_AT, 204619_S_AT,215646_S_AT, 209835_X_AT, 212372_AT, 204035_AT, 203

5_AT, 204205_S_AT, 208937_S_AT, 1555759_A_AT, 217279_X_AT, 211571_S_AT,202539_S_AT, 212464_S_AT GOTERM_(—) 202540_S_AT, 223723_AT, 227069_AT,219028_AT, 212298_AT, 204872_AT, 212014_X_AT, 221731_X_AT, 216

34_AT, CC_ALL 203923_S_AT, 219412_AT, 207674_AT, 217997_AT, 209

03_S_AT, 23

681_AT, 228648_AT, 226545_AT, 203729_AT, 217173_S_AT, 2044

9_S_AT, 205505_AT, 204620_S_AT, 220307_AT, 223303_AT, 211307_S_AT, 2160

0_S_AT, 201590_X_AT, 232649_AT, 203922_S_AT, 2186

6_S_AT, 221825_AT, 1552914_A_AT, 203104_AT, 223562_S_AT, 202756_S_AT,228766_AT, 224674_AT, 214211_AT, 214581_X_AT, 20

926_AT, 224967_AT, 63825_AT, 205463_S_AT, 211719_X_AT, 209949_AT,223501_AT, 229

30_AT, 205099_S_AT, 1557905_S_AT, 209670_AT, 215

36_S_AT, 235944_AT, 23

542_AT, 217074_S_AT, 209047_AT, 240076_AT, 217996_AT, 1554992_AT,221840_AT, 201626_AT, 219926_AT, 211676_S_AT, 225

42_AT, 1554600_S_AT, 23

669_AT, 204257_AT, 203233_AT, 2249

9_AT, 204105_S_AT, 239761_AT, 201243_S_AT, 204912_AT, 23863

_AT, 222

77_AT, 24193

_AT, 209079_X_AT, 212062_AT, 22

0

3_AT, 202434_S_AT, 204222_S_AT, 2064

_S_AT, 220066_AT, 228640_AT, 205542_AT, 204359_AT, 203665_AT,204736_S_AT, 205891_AT, 20274

_AT, 208816_X_AT, 239519_AT, 209835_X_AT, 208161_S_AT, 218856_AT,225116_AT, 204715_AT, 223502_S_AT, 256345_AT, 2120

6_AT, 2239

9_AT, 203

7_S_AT, 2029

_S_AT, 204774_AT, 202539_S_AT, 227240_AT, 210427_X_AT, 2621

_AT, 204661_AT, 20074

_S_AT, 225

09_AT, 204401_AT, 2026

6_S_AT, 222062_AT, 210512_S_AT, 2251

_AT, 217552_X_AT, 211527_X_AT, 202071_AT, 224990_AT, 225325_AT,220313_AT, 20571

_AT, 203935_AT, 210258_AT, 15565

3_A_AT, 201995_AT, 229797_AT, 226302_AT, 203411_S_AT, 21017

_AT, 2156

_AT, 20509

_AT, 2104

5_X_AT, 229221_AT, 210136_AT, 209555_S_AT, 202435_S_AT, 211066_X_AT,216971_S_AT, 210916_S_AT, 2244

0_S_AT, 219225_AT, 202828_S_AT, 214255_AT, 242871_AT, 236561_AT,230360_AT, 201925_S_AT, 228490_AT, 207610_S_AT, 212099_AT, 213577_AT,229937_X_AT, 214830_AT, 227052_AT, 225115_AT, 212977_AT, 203508_AT,230925_AT, 210

45_S_AT, 243556_AT, 201005_AT, 206033_S_AT, 201242_S_AT, 233220_AT,207819_S_AT, 242907_AT, 209122_AT, 160020_AT, 237252_AT, 212171_X_AT,214297_AT, 210133_AT, 22

910_AT, 214

66_AT, 205534_AT, 34210_AT, 205566_AT, 209994_S_AT, 1552690_A_AT,228754_AT, 21767

_AT, 205717_X_AT, 23

5

1_AT, 201739_AT, 209906_AT, 20

218_AT, 210513_S_AT, 204619_S_AT, 215646_S_AT, 25920_AT, 211030_S_AT, 20

121_S_AT, 235295_AT, 201313_AT, 239451_AT, 204881_S_AT, 225097_AT,219994_AT, 217279_X_AT, 201125_S_AT, 201627_S_AT, 201069_AT,211924_S_AT, 203217_S_AT, 213763_AT, 206171_AT, 241954_AT, 203939_AT,243

94_AT, 21342

_S_AT, 202436_S_AT, 204490_S_AT, 219386_S_AT, 209921_AT, 225337_AT, 2204

4_AT, 209146_AT, 22536

_AT, 241773_AT, 22

762_AT, 209392_AT, 224859_AT, 201625_S_AT, 201324_AT, 209993_AT,201012_AT, 212464_S_AT, 216442_X_AT, 2271

0_AT, 213503_X_AT, 241722_X_AT, 228708_AT, 214724_AT, 227107_AT,211661_X_AT, 225207_AT, 226931_AT, 2193

5_AT, 203548_S_AT, 202

27_S_AT, 223092_AT, 205419_AT,

7100_AT, 1562467_AT, 210

39_S_AT, 235299_AT, 224701_AT, 219332_AT, 202437_S_AT, 20206

_S_AT, 212372_AT, 203

_AT, 22379

_AT, 212096_S_AT, 2120

9_AT, 22

696_AT, 218223_S_AT, 241929_AT, 202067_S_AT, 219434_AT, 211571_S_ATKEGG_(—) 214581_X_AT, 204912_AT, 212171_X_AT, 39402_AT, 205463_S_AT,210233_AT, 1405_I_AT, PATHWAY 226218_AT, 223501_AT, 229830_AT,205099_S_AT, 205067_AT, 202859_X_AT, 236561_AT, 210512_S_AT, 221463_AT,211527_X_AT, 204655_AT, 210513_S_AT, 211676_S_AT, 218856_AT,223502_S_AT, 203935_AT, 203104_AT, 203233_AT, 203508_AT, 204436_AT,1555759_A_AT, 205098_AT GOTERM_(—) 201464_X_AT, 210495_X_AT, 229221_AT,201465_S_AT, 201069_AT, 212298_AT, 221841_S_AT, BP_ALL 211924_S_AT,212014_X_AT, 221731_X_AT, 201473_AT, 222877_AT, 241938_AT, 210916_S_AT,235739_AT, 206472_S_AT, 211962_S_AT, 202828_S_AT, 1556901_AT,209803_S_AT, 205067_AT, 202284_S_AT, 202859_X_AT, 236561_AT, 200878_AT,204489_S_AT, 216017_AT, 203665_AT, 204736_S_AT, 204490_S_AT,204620_S_AT, 208816_X_AT, 212099_AT, 201149_S_AT, 201147_S_AT,239519_AT, 201590_X_AT, 209835_X_AT, 204653_AT, 201466_S_AT, 204035_AT,212124_AT, 208937_S_AT, 210845_S_AT, 228762_AT, 201005_AT, 212464_S_AT,160020_AT, 216442_X_AT, 216248_S_AT, 214297_AT, 213503_X_AT,212171_X_AT, 39402_AT, 204622_X_AT, 205463_S_AT, 210427_X_AT, 214866_AT,211719_X_AT, 226218_AT, 229830_AT, 202191_S_AT, 218559_S_AT,1557905_S_AT, 202686_S_AT, 202827_S_AT, 222670_S_AT, 210512_S_AT,211527_X_AT, 201150_S_AT, 204465_S_AT, 201148_S_AT, 203140_AT,220266_S_AT, 213281_AT, 215646_S_AT, 204619_S_AT, 210513_S_AT,212372_AT, 203935_AT, 204105_S_AT, 227697_AT, 201995_AT, 212803_AT,225557_AT, 210173_AT, 217279_X_AT, 211571_S_AT GOTERM_(—) 201464_X_AT,201465_S_AT, 229221_AT, 202435_S_AT, 216243_S_AT, 212014_X_AT,201473_AT, BP_ALL 210916_S_AT, 235739_AT, 202828_S_AT, 205067_AT,202859_X_AT, 236561_AT, 202284_S_AT, 209827_S_AT, 217173_S_AT,204489_S_AT, 201565_S_AT, 201147_S_AT, 213577_AT, 213562_S_AT,210845_S_AT, 201242_S_AT, 233220_AT, 207819_S_AT, 209122_AT, 237252_AT,160020_AT, 212171_X_AT, 216248_S_AT, 39402_AT, 205463_S_AT, 1405_I_AT,201566_X_AT, 214866_AT, 204058_AT, 229830_AT, 205099_S_AT, 209994_S_AT,1557905_S_AT, 239818_X_AT, 217678_AT, 209047_AT, 221463_AT, 201150_S_AT,201148_S_AT, 209906_AT, 209218_AT, 204059_S_AT, 217757_AT, 213281_AT,210513_S_AT, 238669_AT, 235295_AT, 201313_AT, 239451_AT, 37028_AT,217279_X_AT, 201243_S_AT, 201069_AT, 221841_S_AT, 211924_S_AT,222877_AT, 201041_S_AT, 202434_S_AT, 212657_S_AT, 220066_AT, 202014_AT,200878_AT, 203665_AT, 204490_S_AT, 202436_S_AT, 201149_S_AT,209835_X_AT, 209922_AT, 204715_AT, 201466_S_AT, 204035_AT, 203887_S_AT,208937_S_AT, 209392_AT, 209993_AT, 204622_X_AT, 241722_X_AT,218934_S_AT, 227107_AT, 211661_X_AT, 210512_S_AT, 202827_S_AT,211527_X_AT, 1562467_AT, 210839_S_AT, 220266_S_AT, 202241_AT, 204655_AT,209189_AT, 202437_S_AT, 202068_S_AT, 201044_X_AT, 203888_AT,1556583_A_AT, 227697_AT, 1555759_A_AT, 202067_S_AT, 205098_AT GOTERM_(—)201464_X_AT, 201465_S_AT, 229221_AT, 202435_S_AT, 216243_S_AT,212014_X_AT, 201473_AT, BP_ALL 210916_S_AT, 201041_S_AT, 235739_AT,202434_S_AT, 212657_S_AT, 202828_S_AT, 205067_AT, 202284_S_AT,236561_AT, 220066_AT, 202014_AT, 217173_S_AT, 204489_S_AT, 203665_AT,204490_S_AT, 202436_S_AT, 201149_S_AT, 201147_S_AT, 201565_S_AT,209835_X_AT, 213577_AT, 204715_AT, 201466_S_AT, 213562_S_AT,203887_S_AT, 208937_S_AT, 233220_AT, 207819_S_AT, 209122_AT, 160020_AT,237252_AT, 216248_S_AT, 39402_AT, 205463_S_AT, 204622_X_AT, 241722_X_AT,1405_I_AT, 201566_X_AT, 218934_S_AT, 204058_AT, 229830_AT, 227107_AT,211661_X_AT, 1557905_S_AT, 239818_X_AT, 202827_S_AT, 209047_AT,1563467_AT, 201150_S_AT, 201148_S_AT, 209218_AT, 204059_S_AT, 217757_AT,213281_AT, 202241_AT, 204655_AT, 209189_AT, 202437_S_AT, 202068_S_AT,201044_X_AT, 238669_AT, 203888_AT, 235295_AT, 201313_AT, 1556583_A_AT,227697_AT, 37028_AT, 1555759_A_AT, 217279_X_AT, 202067_S_AT GOTERM_(—)201464_X_AT, 202540_S_AT, 229221_AT, 227069_AT, 201465_S_AT, 212298_AT,212014_X_AT, BP_ALL 201473_AT, 210916_S_AT, 208960_S_AT, 206472_S_AT,202828_S_AT, 205067_AT, 209803_S_AT, 236561_AT, 202859_X_AT,202284_S_AT, 204489_S_AT, 216017_S_AT, 212099_AT, 201565_S_AT,201147_S_AT, 201590_X_AT, 204653_AT, 1555832_S_AT, 210845_S_AT,208961_S_AT, 160020_AT, 212171_X_AT, 214297_AT, 224967_AT, 39402_AT,205463_S_AT, 201566_X_AT, 228964_AT, 214866_AT, 229830_AT, 1557905_S_AT,206835_AT, 222670_S_AT, 201150_S_AT, 201148_S_AT, 213281_AT, 224606_AT,210513_S_AT, 1554600_S_AT, 204881_S_AT, 212803_AT, 225557_AT,217279_X_AT, 201069_AT, 37152_AT, 221841_S_AT, 211924_S_AT, 222877_AT,241938_AT, 211962_S_AT, 1566901_AT, 200878_AT, 204736_S_AT, 203665_AT,204490_S_AT, 208816_X_AT, 201149_S_AT, 239519_AT, 209835_X_AT,201466_S_AT, 204035_AT, 212086_X_AT, 220484_AT, 212124_AT, 208937_S_AT,228762_AT, 230529_AT, 201324_AT, 202539_S_AT, 201012_AT, 213503_X_AT,210427_X_AT, 226218_AT, 218559_S_AT, 202686_S_AT, 219845_AT,210512_S_AT, 202827_S_AT, 205419_AT, 211527_X_AT, 1562467_AT,204465_S_AT, 203140_AT, 220255_S_AT, 220935_S_AT, 212372_AT, 203935_AT,212089_AT, 201995_AT, 227697_AT, 229797_AT, 203411_S_AT, 210173_AT,203320_AT GOTERM_(—) 201464_X_AT, 213891_S_AT, 227069_AT, 201465_S_AT,219028_AT, 212298_AT, 210136_AT, BP_ALL 216834_AT, 201471_S_AT,235739_AT, 202828_S_AT, 205067_AT, 236561_AT, 202859_X_AT, 202284_S_AT,201170_S_AT, 203729_AT, 228490_AT, 216017_S_AT, 212099_AT, 201147_S_AT,201565_S_AT, 201590_X_AT, 203753_AT, 221815_AT, 1552914_A_AT, 225115_AT,222146_S_AT, 203508_AT, 205312_AT, 201005_AT, 233220_AT, 210095_S_AT,214211_AT, 160020_AT, 212171_X_AT, 216248_S_AT, 63825_AT, 39402_AT,205463_S_AT, 1405_I_AT, 201566_X_AT, 228964_AT, 223501_AT, 223398_AT,229830_AT, 212387_AT, 205566_AT, 218502_S_AT, 206835_AT, 239818_X_AT,222670_S_AT, 208436_S_AT, 200920_S_AT, 201150_S_AT, 201148_S_AT,202768_AT, 217757_AT, 213281_AT, 210513_S_AT, 238669_AT, 203233_AT,239451_AT, 212386_AT, 225097_AT, 219257_S_AT, 212803_AT, 217591_AT,217279_X_AT, 37152_AT, 221841_S_AT, 224218_S_AT, 213763_AT, 1566901_AT,220066_AT, 203939_AT, 202388_AT, 205891_AT, 203665_AT, 204998_S_AT,208816_X_AT, 201149_S_AT, 239519_AT, 225116_AT, 201466_S_AT,223502_S_AT, 225337_AT, 212143_S_AT, 204035_AT, 225368_AT, 202988_S_AT,208937_S_AT, 222651_S_AT, 224859_AT, 201012_AT, 205681_AT, 213503_X_AT,204622_X_AT, 241722_X_AT, 210427_X_AT, 226218_AT, 200748_S_AT,218559_S_AT, 222062_AT, 203940_S_AT, 200921_S_AT, 219845_AT, 219908_AT,210512_S_AT, 202827_S_AT, 87100_AT, 211527_X_AT, 203140_AT, 220266_S_AT,202241_AT, 204655_AT, 203935_AT, 210258_AT, 227697_AT, 1555759_A_AT,226302_AT, 223394_AT GOTERM_(—) 205891_AT, 203140_AT, 212171_X_AT,213503_X_AT, 217757_AT, 205463_S_AT, 208816_X_AT, BP_ALL 1405_I_AT,204655_AT, 210513_S_AT, 210427_X_AT, 201590_X_AT, 229830_AT,1552914_A_AT, 204035_AT, 203508_AT, 210512_S_AT, 1555759_A_AT,202859_X_AT, 211527_X_AT, 209827_S_AT, 203939_AT, 224859_AT, 233220_ATGOTERM_(—) 201464_X_AT, 210495_X_AT, 223723_AT, 201465_S_AT, 37152_AT,210136_AT, 212298_AT, BP_ALL 209555_S_AT, 202435_S_AT, 227948_AT,211924_S_AT, 203074_AT, 241938_AT, 202434_S_AT, 206488_S_AT, 214255_AT,205067_AT, 202284_S_AT, 236561_AT, 200878_AT, 201925_S_AT, 201170_S_AT,203729_AT, 217173_S_AT, 216017_S_AT, 205891_AT, 203665_AT, 202436_S_AT,208816_X_AT, 201565_S_AT, 239519_AT, 201590_X_AT, 201466_S_AT,223502_S_AT, 215602_AT, 203887_S_AT, 228766_AT, 210845_S_AT, 241773_AT,201005_AT, 201324_AT, 212464_S_AT, 214211_AT, 237252_AT, 216442_X_AT,213503_X_AT, 212171_X_AT, 39402_AT, 241722_X_AT, 1405_I_AT, 201566_X_AT,210427_X_AT, 214866_AT, 211719_X_AT, 226218_AT, 223501_AT, 204661_AT,202191_S_AT, 34210_AT, 200748_S_AT, 205099_S_AT, 204401_AT, 206835_AT,200921_S_AT, 235944_AT, 203548_S_AT, 210512_S_AT, 200920_S_AT,208436_S_AT, 211527_X_AT, 1562467_AT, 209906_AT, 1554992_AT, 203140_AT,213281_AT, 204655_AT, 202437_S_AT, 210513_S_AT, 202068_S_AT,1565754_X_AT, 238669_AT, 212372_AT, 203888_AT, 1565752_AT, 239451_AT,1556583_A_AT, 219257_S_AT, 212803_AT, 1555759_A_AT, 241929_AT,202067_S_AT, 215688_AT, 205098_AT, 223394_AT GOTERM_(—) 160020_AT,210495_X_AT, 216442_X_AT, 201069_AT, 212171_X_AT, 213503_X_AT,210427_X_AT, CC_ALL 211719_X_AT, 221731_X_AT, 202828_S_AT, 235944_AT,210512_S_AT, 202827_S_AT, 211527_X_AT, 204475_AT, 201150_S_AT,201148_S_AT, 213428_S_AT, 204359_AT, 204620_S_AT, 229004_AT,208816_X_AT, 201149_S_AT, 210513_S_AT, 201147_S_AT, 215646_S_AT,204619_S_AT, 201590_X_AT, 202756_S_AT, 228873_AT, 216546_S_AT,217279_X_AT, 211571_S_AT, 212464_S_AT GOTERM_(—) 201464_X_AT, 160020_AT,201465_S_AT, 229221_AT, 201069_AT, 212171_X_AT, 213503_X_AT, BP_ALL212298_AT, 214297_AT, 39402_AT, 205463_S_AT, 221841_S_AT, 212014_X_AT,210427_X_AT, 201473_AT, 222877_AT, 210916_S_AT, 229830_AT, 1557905_S_AT,202828_S_AT, 1566901_AT, 205067_AT, 210512_S_AT, 202827_S_AT,202859_X_AT, 211527_X_AT, 200878_AT, 204489_S_AT, 203665_AT,204736_S_AT, 204490_S_AT, 220266_S_AT, 213281_AT, 212099_AT,208816_X_AT, 210513_S_AT, 239519_AT, 209835_X_AT, 201590_X_AT,204653_AT, 201466_S_AT, 212372_AT, 204035_AT, 203935_AT, 208937_S_AT,217279_X_AT, 201005_AT GOTERM_(—) 202540_S_AT, 160020_AT, 229221_AT,210495_X_AT, 216442_X_AT, 37152_AT, 212298_AT, BP_ALL 216248_S_AT,39402_AT, 204622_X_AT, 1405_I_AT, 212014_X_AT, 221731_X_AT, 211719_X_AT,222877_AT, 210916_S_AT, 204268_AT, 235739_AT, 223220_S_AT, 1557905_S_AT,200921_S_AT, 202828_S_AT, 205067_AT, 202859_X_AT, 202827_S_AT,236561_AT, 200920_S_AT, 209827_S_AT, 204489_S_AT, 204490_S_AT,204620_S_AT, 204655_AT, 239519_AT, 204619_S_AT, 215646_S_AT,209835_X_AT, 212372_AT, 204035_AT, 203935_AT, 204105_S_AT, 208937_S_AT,1555759_A_AT, 217279_X_AT, 211571_S_AT, 202539_S_AT, 212464_S_ATGOTERM_(—) 202540_S_AT, 160020_AT, 229221_AT, 210495_X_AT, 216442_X_AT,37152_AT, 21229

_AT BP_ALL 216248_S_AT, 39402_AT, 204622_X_AT, 1405_I_AT, 212014_X_AT,221731_X_AT, 211719_X_AT, 222877_AT, 210916_S_AT, 204268_AT, 235739_AT,223220_S_AT, 1557905_S_AT, 200921_S_AT, 202

28_S_AT, 205067_AT, 202

59_X_AT, 202

27_S_AT, 236561_AT, 200920_S_AT, 209827_S_AT, 204489_S_AT, 204490_S_AT,204620_S_AT, 204655_AT, 239519_AT, 204615_S_AT, 215646_S_AT,209835_X_AT, 212372_AT, 204035_AT, 203935_AT, 204105_S_AT, 208937_S_AT,1555759_A_AT, 217279_X_AT, 211571_S_AT, 202539_S_AT, 212464_S_ATGOTERM_(—) 201464_X_AT, 201465_S_AT, 37152_AT, 209555_S_AT, 39402_AT,1405_I_AT, 201566_X_AT, BP_ALL 201473_AT, 226218_AT, 204923_AT,206488_S_AT, 200921_S_AT, 1566901_AT, 205067_AT, 203548_S_AT,200920_S_AT, 15

9149_AT, 203751_X_AT, 2132

1_AT, 212099_AT, 204655_AT, 201565_S_AT, 201466_S_AT, 212143_S_AT,1552914_A_AT, 203935_AT, 204105_S_AT, 203233_AT, 227697_AT, 228766_AT,203752_AT, 219257_S_AT, 1555759_A_AT, 241929_AT, 224859_AT, 210095_S_ATGOTERM_(—) 202540_S_AT, 22

221_AT, 2270

_AT, 223723_AT, 2122

_AT, 20

55_S_AT, 212024_X_AT, 221731_X_AT, CC_ALL 20

23_S_AT, 212066_X_AT, 22091

_S_AT, 207

74_AT, 239225_AT, 2244

0_S_AT, 202828_S_AT, 2142

_AT, 242

71_AT, 23

1_AT, 230

60_AT, 236561_AT, 226545_AT, 201

25_S_AT, 203729_AT, 227173_S_AT, 2044

_S_AT, 22

90_AT, 202610_S_AT, 205505_AT, 220307_AT, 204

20_S_AT, 212099_AT, 211307_S_AT, 21

0_S_AT, 232649_AT, 233577_AT, 203922_S_AT, 21

_S_AT, 229

37_X_AT, 221

15_AT, 214

0_AT, 2270

2_AT, 1552

_A_AT, 20210

_AT, 213

62_S_AT, 212977_AT,

02754_S_AT, 22

6_AT, 20350

_AT, 210

5_S_AT, 20

033_S_AT, 201005_AT, 201242_S_AT, 233220_AT, 207

_S_AT, 224674_AT, 2145

_X_AT, 237252_AT, 160020_AT, 2142

7_AT, 224

67_AT,

3125_AT, 210

33_AT, 22

10_AT, 20

_AT, 214

_AT, 223502_AT, 205534_AT, 34120_AT, 2050

_S_AT, 205566_AT, 200994_S_AT, 1552630_A_AT, 1557905_S_AT, 22

754_AT, 209670_AT, 22

42_AT, 215

36_S_AT, 217

7

_AT, 205717_A_AT, 217078_S_AT, 240076_AT, 209047_AT, 209906_AT, 20921

_AT, 221

40_AT, 204619_S_AT, 215616_S_AT, 201626_AT, 2120

0_S_AT, 20

20_AT, 219926_AT, 20

121_S_AT, 21167

_S_AT, 2352

5_AT, 204257_AT, 203233_AT, 224

9_AT, 204

05_S_AT, 20

81_S_AT, 201125_S_AT, 217279_X_AT, 20

677_S_AT, 23

762_AT, 201243_S_AT, 204912_AT, 238

_AT, 211

24_S_AT, 222

77_AT, 203217_S_AT, 209019_X_AT, 212062_AT, 228083_AT, 204222_S_AT, 20

88_S_AT, 20

171_AT, 2

2954_AT, 22

640_AT, 20

9_AT, 205542_AT, 24

_AT, 2042

_AT, 205

91_AT, 2047

_S_AT, 2

4490_S_AT, 23

9_AT, 219

_S_AT, 20

35_X_AT, 208161_S_AT, 20

21_AT, 218856_AT, 204715_AT, 223502_S_AT, 225337_AT, 236345_AT, 2204

4_AT, 203

7_S_AT, 22

_AT, 20

46_AT, 20

2_AT, 2287

2_AT, 241773_AT, 224

_AT, 20

53_AT, 201324_AT, 201625_S_AT, 202

_S_AT, 204774_AT, 227180_AT, 241722_X_AT, 22

70

_AT, 226228_AT, 20

61_AT, 225

09_AT, 227107_AT, 204401_AT, 2116

1_X_AT, 222062_AT, 202

8_S_AT, 2269

1_AT, 21

85_AT, 20354

_S_AT, 22

0

2_AT, 217552_X_AT, 202

27_S_AT, 205419_AT,

71

0_AT, 202071_AT, 2108

_S_AT, 22

90_AT, 235299_AT, 225325_AT, 2020

_S_AT, 220311_AT, 205714_AT, 20

_AT, 20

5_AT, 2237

_AT, 2286

_AT, 201995_AT, 15565

3_A_AT, 22

297_AT, 226302_AT, 241

28_AT 210173_AT,

020

7_S_AT, 215434_AT, 211572_S_AT, 2050

_AT GOTERM_(—) 20

4

4_X_AT, 201465_S_AT, 229221_AT, 227069_AT, 210495_X_AT, 212296_AT,210136_AT, BP_ALL 212014_X_AT, 221731_X_AT, 201473_AT, 210916_S_AT,201471_S_AT, 235739_AT, 204960_S_AT, 202828_S_AT, 242871_AT, 22

64

_AT, 236561_AT, 230360_AT, 156

149_AT, 20

9_S_AT, 216017_S_AT, 208891_AT, 212099_AT, 204620_S_AT, 201565_S_AT,232619_AT, 1555832_S_AT, 243556_AT, 204961_S_AT, 210095_S_AT, 233220_AT,160020_AT, 212171_X_AT, 214297_AT, 21624

_S_AT, 201565_X_AT, 211719_X_AT, 228564_AT, 202191_S_AT, 1557505_S_AT,201751_X_AT, 155

92_AT, 213281_AT, 224606_AT, 215646_S_AT, 204619_S_AT, 210513_S_AT,204105_S_AT, 203752_S_AT, 212803_AT, 217279_X_AT, 37152_AT, 221841_S_AT,221

77_AT, 24193

_AT, 211

2_S_AT, 1566901_AT, 204141_AT, 200678_AT, 2023

_AT, 204736_S_AT, 204490_S_AT, 2049

_S_AT, 239519_AT, 209835_X_AT, 212190_AT, 201466_S_AT, 212143_S_AT, 2204

4_AT, 212124_AT, 201324_AT, 201012_AT, 212464_S_AT, 216

42_X_AT, 204622_X_AT, 241722_X_AT, 227240_AT, 226218_AT, 208893_S_AT,219

45_AT, 210512_S_AT, 202827_S_AT, 205419_AT, 211917_X_AT, 1562467_AT,204465_S_AT, 203240_AT, 208

2_S_AT, 2202

6_S_AT, 220935_S_AT, 212372_AT, 201935_AT, 225797_AT, 210171_AT,211571_S_AT, 203920_AT, 215

_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 219028_AT, 212298_AT,216834_AT, 242794_AT, 213763_AT, BP_ALL 206472_S_AT, 203882_AT,206171_AT, 226389_S_AT, 202859_X_AT, 236561_AT, 205891_AT, 207610_S_AT,239519_AT, 225126_AT, 201466_S_AT, 203104_AT, 225115_AT, 212977_AT,223939_AT, 203508_AT, 225368_AT, 202988_S_AT, 208937_S_AT, 209392_AT,241773_AT, 233220_AT, 201012_AT, 212171_AT, 205463_S_AT, 1405_I_AT,235457_AT, 214724_AT, 226218_AT, 229830_AT, 205099_S_AT, 211661_X_AT,202686_S_AT, 222062_AT, 219908_AT, 210512_S_AT, 228186_S_AT, 205419_AT,211527_X_AT, 210839_S_AT, 244414_AT, 209906_AT, 242405_AT, 213281_AT,221840_AT, 204655_AT, 210513_S_AT, 209189_AT, 214054_AT, 203037_S_AT,220313_AT, 205718_AT, 225738_AT, 203935_AT, 210258_AT, 225097_AT,219257_S_AT, 1555759_A_AT, 210173_AT, 225557_AT, 201125_S_AT, 20509

_AT GOTERM_(—) 204912_AT, 209555_S_AT, 217757_AT, 210233_AT,211676_S_AT, 226218_AT, 205099_S_AT, MF_ALL 203104_AT, 203935_AT, 2064

_S_AT, 203233_AT, 222062_AT, 228766_AT, 203508_AT, 236361_AT, 241929_AT,205098_AT GOTERM_(—) 237252.AT, 210495_X_AT, 216442_X_AT, 229221_AT,37152_AT, 209555_S_AT, 39402_AT, BP_ALL 205463_S_AT, 211924_S_AT,212014_X_AT, 214866_AT, 211719_X_AT, 203074_AT, 210916_S_AT, 229830_AT,206488_S_AT, 1557905_S_AT, 208960_S_AT, 235944_AT, 205067_AT,201150_S_AT, 204465_S_AT, 201148_S_AT, 204489_S_AT, 203665_AT,204490_S_AT, 224606_AT, 201149_S_AT, 201147_S_AT, 209835_X_AT,212372_AT, 203888_AT, 203887_S_AT, 1555832_S_AT, 228766_AT, 210845_S_AT,241929_AT, 201005_AT, 208961_S_AT, 212464_S_AT GOTERM_(—) 202540_S_AT,210495_X_AT, 229221_AT, 37152_AT, 212298_AT, 212014_X_AT, 211924_S_AT,BP_ALL 221731_X_AT, 222877_AT, 210916_S_AT, 204268_AT, 235739_AT,223220_S_AT, 202828_S_AT, 205067_AT, 202859_X_AT, 236561_AT,209827_S_AT, 204489_S_AT, 204490_S_AT, 204620_S_AT, 239519_AT,209835_X_AT, 204035_AT, 208937_S_AT, 209392_AT, 210845_S_AT, 201005_AT,202539_S_AT, 201012_AT, 212464_S_AT, 160020_AT, 216442_X_AT,216248_S_AT, 39402_AT, 204622_X_AT, 1405_I_AT, 211719_X_AT, 214866_AT,1557905_S_AT, 200921_S_AT, 202827_S_AT, 200920_S_AT, 210839_S_AT,204655_AT, 215646_S_AT, 204619_S_AT, 203037_S_AT, 212372_AT, 203935_AT,204105_S_AT, 1555759_A_AT, 217279_X_AT, 211571_S_AT GOTERM_(—)210495_X_AT, 216442_X_AT, 210136_AT, 212171_X_AT, 212298_AT, 39402_AT,227948_AT, BP_ALL 211719_X_AT, 202191_S_AT, 203940_S_AT, 200921_S_AT,214255_AT, 205067_AT,210512_S_AT, 200920_S_AT, 211527_X_AT, 203665_AT,205891_AT, 212099_AT, 239519_AT, 210513_S_AT, 1565754_X_AT, 212372_AT,1565752_AT, 204105_S_AT, 215602_AT, 219257_S_AT, 208937_S_AT,212464_S_AT GOTERM_(—) 201464_X_AT, 213

91_S_AT, 229221_AT, 201465_S_AT, 219028_AT, 212298_AT, 209555_S_AT,BP_ALL 212014_X_AT, 201473_AT, 211352_S_AT, 210916_S_AT, 201471_S_AT,235739_AT, 234840_S_AT, 205067_AT, 217997_AT, 236561_AT, 202859_X_AT,2022

4_S_AT, 209

27_S_AT, 201925_S_AT, 1569149_AT, 204489_S_AT, 212099_AT, 201147_S_AT,201565_S_AT, 203753_AT, 207700_S_AT, 1552914_A_AT, 225215_AT,1555832_S_AT, 228766_AT, 222146_S_AT, 205312_AT, 243556_AT, 20

961_S_AT, 210095_S_AT, 212171_X_AT, 216248_S_AT, 39402_AT, 205463_S_AT,1405_I_AT, 235457_AT, 201566_X_AT, 22

964_AT, 223501_AT, 229

10_AT, 212387_AT, 202086_AT, 1557905_S_AT, 222670_S_AT, 200920_S_AT, 20

436_S_AT, 201150_S_AT, 203751_X_AT, 217996_AT, 20114

_S_AT, 209906_AT, 1554992_AT, 2132

1_AT, 224606_AT, 210513_S_AT, 1565754_X_AT, 225842_AT, 238669_AT,2353295_AT, 1565752_AT, 203233_AT, 204105_S_AT, 212386_AT, 225097_AT,203752_S_AT, 219257_S_AT, 225557_AT, 37152_AT, 22794

_AT, 221841_S_AT, 242794_AT, 21294

_AT, 204923_AT, 201041_S_AT, 206488_S_AT, 213763_AT, 1554453_AT,1566901_AT, 220066_AT, 20087

_AT, 205891_AT, 203663_AT, 204490_S_AT, 201149_S_AT, 239519_AT,209835_X_AT, 225116_AT, 204715_AT, 206157_AT, 201466_S_AT, 223502_S_AT,212143_S_AT, 204035_AT, 215602_AT, 212124_AT, 225368_AT, 241273_AT,224859_AT, 218501_AT, 243797_AT, 204622_X_AT, 227240_AT, 22621

_AT, 218559_S_AT, 227107_AT, 204401_AT, 222062_AT, 200921_S_AT, 20354

_S_AT, 217552_X_AT, 210512_S_AT, 211527_X_AT, 244414_AT, 203140_AT,242405_AT, 220266_S_AT, 204655_AT, 1552553_A_AT, 2091

9_AT, 201044_X_AT, 203935_AT, 227697_AT, 1555759_A_AT, 241929_AT,215688_AT, 223394_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 37152_AT, 20

555_S_AT, 1405_I_AT, 201565_X_AT, 201473_AT, BP_ALL 226218_AT,204923_AT, 206488_S_AT, 200921_S_AT, 1566901_AT, 203548_S_AT,200920_S_AT, 203751_X_AT, 1569149_AT, 213281_AT, 204655_AT, 201565_S_AT,201466_S_AT, 212143_S_AT, 1552914_A_AT, 203935_AT, 203233_AT,204205_S_AT, 227697_AT, 22

76

_AT, 203752_S_AT, 1555759_A_AT, 241929_AT, 224859_AT, 210095_S_ATGOTERM_(—) 201464_X_AT, 201465_S_AT, 229221_AT, 227069_AT, 210495_X_AT,212298_AT, 210136_AT, BP_ALL 212014_X_AT, 221731_X_AT, 201473_AT,210916_S_AT, 201471_S_AT, 235739_AT, 208960_S_AT, 202828_S_AT, 242

71_AT, 22

648;_AT, 236561_AT, 230360_AT, 1569149_AT, 204489_S_AT, 216017_S_AT, 208

91_AT, 212099_AT, 204620_S_AT, 201565_S_AT, 232649_AT, 1555

32_S_AT, 201005_AT, 243556_AT, 208961_S_AT, 210095_S_AT, 233220_AT,160020_AT, 214297_AT, 212171_X_AT, 216248_S_AT, 201566_X_AT,211719_X_AT, 228964_AT, 202193_S_AT, 1557905_S_AT, 203751_X_AT,1554992_AT, 213281_AT, 224606_AT, 215646_S_AT, 204619_S_AT, 210513_S_AT,204105_S_AT, 203752_S_AT, 212803_AT, 217279_X_AT, 37152_AT, 221

41_AT, 222

77_AT, 24193

_AT, 211962_S_AT, 1566901_AT, 204141_AT, 200878_AT, 2025

_AT, 204736_S_AT, 204490_S_AT, 2049

_S_AT, 239519_AT, 209835_X_AT, 212190_AT, 201466_S_AT, 212143_S_AT,220484_AT, 212124_AT, 201324_AT, 201012_AT, 212464_S_AT, 216

42_X_AT, 204622_X_AT, 241722_X_AT, 227240_AT, 22621

_AT, 20889

_S_AT, 219

45_AT, 210512_S_AT, 202

27_S_AT, 205419_AT, 211527_X_AT, 1562467_AT, 2044

5_S_AT, 203140_AT, 208

92_S_AT, 220266_S_AT, 220935_S_AT, 212372_AT, 203935_AT, 229797_AT,210173_AT, 211571_S_AT, 203320_AT, 215

_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 37152_AT, 212298_AT, 210136_AT,209555_S_AT, 221841_S_AT, BP_ALL 1405_I_AT, 201566_X_AT, 201473_AT,226218_AT, 218559_S_AT, 204923_AT, 206488_S_AT, 200921_S_AT, 1566901_AT,203548_S_AT, 236561_AT, 222670_S_AT, 200920_S_AT, 1569149_AT,203751_X_AT, 203140_AT, 220266_S_AT, 20499

_S_AT, 220935_S_AT, 213281_AT, 204655_AT, 201565_S_(——)AT, 239519_AT,201466_S_AT, 1552914_A_AT, 212143_S_AT, 2

3935_AT, 203233_AT, 204105_S_AT, 227697_AT, 228766_AT, 203752_AT,1555759_A_AT, 205312_AT, 241929_AT, 224859_AT, 210095_S_AT GOTERM_(—)202540_S_AT, 202464_X_AT, 21

1_S_AT, 2014

5_S_AT, 223724_AT, 227069_AT, 21902

_AT, 2122

_AT, 212

14_X_AT, BP_ALL 216

34_AT, 22

412_AT, 20

60_S_AT, 217

97_AT, 205067_AT, 20

_X_AT, 201170_S_AT, 20

729_AT, 21712

_S_AT, 2044

_S_AT, 216017_S_AT, 225171_AT, 220

07_AT, 202

_S_AT, 201147_S_AT, 201

0_X_AT, 230266_AT, 20

653_AT, 221815_AT, 1552914_A_AT, 207700_S_AT, 202104_AT, 1555

2_S_AT, 204

_AT, 222144_S_AT, 2287

_AT, 2100

5_S_AT, 214211_AT, 2145

1_X_AT, 2162

_S_AT, 6

25_AT, 205

3_S_AT, 140

_I_AT, 2015

_X_AT, 2

4_AT, 21171

_

_AT, 22

03_AT, 2020

_AT, 2173

7_AT, 22

30_AT, 205099_S_AT, 1557905_S_AT, 21

02_S_AT, 20

5_AT, 235

4_AT, 222

70_S_AT, 200

20_S_AT, 2191

3_S_AT, 20

_S_AT, 2278

_AT, 2087

_X_AT, 201150_S_AT, 20114

_S_AT, 1554

2_AT, 217757_AT, 2132

1_AT, 15

5754_X_AT, 2295

_AT, 20

0

_AT, 211

_S_AT, 223

42_AT, 2257

_AT, 214250_S_AT, 20

_AT, 23

_AT, 154

752_AT, 2032

_AT, 20420

_S_AT, 3702

_AT, 20

7

2_S_AT, 225557_AT, 2173

2_AT,

7152_AT, 227943_AT, 242794_AT, 242

34_AT, 201041_S_AT, 204

23_AT, 202434_S_AT, 20

_S_AT, 212562_S_AT, 2251

_AT, 2200

_AT, 200

78_AT, 225144_AT, 202

_AT, 205

1_AT, 2

65_AT, 204734_S_AT, 20

_X_AT, 2

1

_AT, 20

_X_AT, 2

_AT, 225116_AT, 212180_AT, 20

715_AT, 20

4

_S_AT, 22

502_S_AT, 21214

_S_AT, 235602_AT, 22

_AT, 2

67_S_AT, 202

_S_AT, 208

7_S_AT, 222

1_S_AT, 2025

_S_AT, 21

501_AT, 2

7

7_AT, 2272

0_AT, 210427_X_AT, 22

21

_AT, 21

_S_AT, 204

61_AT, 200

_S_AT, 204401_AT, 20

_S_AT, 2220

2_AT, 22

_AT, 227

_AT, 21

_AT, 220512_S_AT, 225

_AT, 217552_X_AT, 212527_X_AT, 202071_AT, 244424_AT, 203

40_AT, 20

52_S_AT, 220

_S_AT, 242405_AT, 202241_AT, 201044_X_AT, 220313_AT, 20

_AT, 2102

_AT, 155636

_A_AT, 201

_AT, 22

302_AT, 215

_AT, 2050

_AT, 210

_X_AT, 229225_AT, 210124_AT, 2

5_S_AT, 229155_AT, 202

_S_AT, 221011_S_AT, 20247

_AT, 20247

_AT, 20

074_AT, 210916_S_AT, 211

2_X_AT, 1555

22_AT, 201471_S_AT, 2357

_AT, 204472_S_AT, 200

2_AT, 226

_S_AT, 2244

_S_AT, 202

_S_AT, 214255_AT, 202

_S_AT, 2

1_AT, 20

27_A_AT, 201525_S_AT, 15

49_AT, 22

90_AT, 207610_S_AT, 20

91_AT, 2120

_AT, 20

75

_AT, 1

2_A_AT, 225125_AT, 212

77_AT, 201

_AT, 20

312_AT, 230

25_AT, 2

0

45_S_AT, 24

_AT, 201005_AT, 20

1_S_AT, 2

20_AT, 2132

_S_AT, 1500

_AT, 227252_AT, 212171_X_AT, 2142

7_AT, 39402_AT, 21023

_AT, 2

457_AT, 214

66_AT, 23

_AT, 2021

1_S_AT, 34210_AT, 2

4_AT, 205566_AT, 2

1

_X_AT, 221463_AT, 20

436_S_AT, 20

06_AT, 20276

_AT, 22

606_AT, 210513_S_AT, 2352

5_AT, 2

451_AT, 200

72_AT, 212

5_AT, 22

0

7_AT, 21

257_S_AT, 21

4_AT, 222

03_AT, 21727

_X_AT, 221

41_S_AT, 234

_AT, 211

24_AT, 2242

_S_AT, 212

_AT, 21

7

_AT, 240

6_AT, 204271_AT, 1554451_AT, 1555

01_AT, 1550

_AT, 20101

_AT, 20

_AT, 2024

_S_AT, 2044

0_S_AT, 20

_S_AT, 20114

_S_AT, 236570_AT, 20

257_AT, 22

37_AT, 2040

5_AT, 212224_AT, 2253

_AT, 200

7_AT, 24177

_AT, 224

_AT, 201324_AT, 200

1_AT, 201012_AT, 212

4_S_AT, 216

2_X_AT, 21

50

_X_AT, 204622_X_AT, 242722_X_AT, 22

70

_AT, 21

_S_AT, 227107_AT, 221

1_X_AT, 20

0_S_AT, 20

1_S_AT, 225207_AT, 200

25_S_AT, 20

_S_AT, 22

_AT, 202

27_S_AT, 20042

_AT,

7200_AT,

0039_S_AT, 1542467_AT, 206571_S_AT, 22

_AT, 224702_AT, 220935_S_AT, 204

5_AT, 15

2553_A_AT, 202437_S_AT, 20

1

_AT, 20

_S_AT, 2140

_AT, 20

0

7_S_AT, 212

72_AT, 203

_AT, 217272_S_AT, 227

7_AT, 15557

_A_AT, 241929_AT, 2020

7_S_AT, 21943

_AT, 20

20_AT, 222

4_AT GOTERM_(—) 201464_X_AT, 237252_AT, 201465_S_AT, 39402_AT,1405_I_AT, 202708_S_AT, 218934_S_AT, BP_ALL 202086_AT, 211661_X_AT,222062_AT, 203882_AT, 239818_X_AT, 205067_AT, 220066_AT, 208436_S_AT,202014_AT, 214453_S_AT, 202241_AT, 213281_AT, 204655_AT, 1552553_A_AT,209189_AT, 211676_S_AT, 229937_X_AT, 201466_S_AT, 206157_AT, 203888_AT,227697_AT, 203887_S_AT, 37028_AT, 205495_S_AT, 1555759_A_AT,208438_S_AT, 213293_S_AT GOTERM_(—) 202540_S_AT, 229221_AT, 227069_AT,223723_AT, 212298_AT, 209555_S_AT, 212014_X_AT, CC_ALL 221731_X_AT,203923_S_AT, 211066_X_AT, 210916_S_AT, 207674_AT, 219225_AT,224480_S_AT, 202828_S_AT, 214255_AT, 242871_AT, 238681_AT, 230360_AT,236561_AT, 201925_S_AT, 203729_AT, 217173_S_AT, 204489_S_AT, 228450_AT,207610_S_AT, 205505_AT, 220307_AT, 204620_S_AT, 211307_S_AT,216080_S_AT, 232649_AT, 213577_AT, 203922_S_AT, 218686_S_AT,229937_X_AT, 214830_AT, 221815_AT, 227052_AT, 1552914_A_AT, 203104_AT,213562_S_AT, 212977_AT, 202756_S_AT, 228766_AT, 203508_AT, 210845_S_AT,206033_S_AT, 201005_AT, 201242_S_AT, 233220_AT, 207819_S_AT, 224674_AT,214581_X_AT, 237252_AT, 160020_AT, 214297_AT, 224967_AT, 63825_AT,210233_AT, 228910_AT, 209949_AT, 214866_AT, 223501_AT, 205534_AT,34210_AT, 205099_S_AT, 205566_AT, 209994_S_AT, 1552690_A_AT,1557905_S_AT, 228754_AT, 209670_AT, 215836_S_AT, 217678_AT, 205717_X_AT,217078_S_AT, 240076_AT, 209047_AT, 209906_AT, 209218_AT, 221840_AT,204619_S_AT, 215646_S_AT, 201626_AT, 211030_S_AT, 205920_AT, 219926_AT,208121_S_AT, 211676_S_AT, 235295_AT, 204257_AT, 203233_AT, 224989_AT,204105_S_AT, 204881_S_AT, 201125_S_AT, 217279_X_AT, 201627_S_AT,239791_AT, 201243_S_AT, 204912_AT, 23

638_AT, 211924_S_AT, 222877_AT, 203217_S_AT, 209079_X_AT, 212062_AT, 22

083_AT, 204222_S_AT, 206488_S_AT, 206171_AT, 241954_AT, 228640_AT,205542_AT, 243894_AT, 204359_AT, 205891_AT, 204736_S_AT, 204490_S_AT,239519_AT, 219386_S_AT, 209835_X_AT, 208161_S_AT, 209921_AT, 218856_AT,204715_AT, 223502_S_AT, 225337_AT, 236345_AT, 220484_AT, 203387_S_AT,223939_AT, 209146_AT, 209392_AT, 228762_AT, 241773_AT, 224859_AT,209993_AT, 201324_AT, 201625_S_AT, 202539_S_AT, 204774_AT, 227180_AT,241722_X_AT, 226218_AT, 204661_AT, 225809_AT, 227107_AT, 20

401_AT, 211661_X_AT, 222062_AT, 202686_S_AT, 226931_AT, 219385_AT,223092_AT, 217552_X_AT, 202827_S_AT, 205419_AT, 87100_AT, 202071_AT,210839_S_AT, 224990_AT, 235299_AT, 225325_AT, 202068_S_AT, 220313_AT,205718_AT, 203888_AT, 203935_AT, 223798_AT, 228696_AT, 201995_AT,1556583_S_AT, 229797_AT, 226302_AT, 241929_AT, 210173_AT, 202067_S_AT,219434_AT, 211571_S_AT, 205098_AT GOTERM_(—) 21

_S_AT, 201464_X_AT, 2

540_X_AT, 2270

_AT, 2

43_S_AT, 21

0

_AT, 2122

_AT, 212014_X_AT, 214

3

_AT, BP_ALL 21

412_AT, 20

40_S_AT, 217997_AT, 2

0

7_AT, 20

_X_AT, 201270_S_AT, 20

7

_AT, 2

_S_AT, 21

17_S_AT, 235171_AT, 220307_AT, 201

_S_AT, 20114

_S_AT, 201

_X_AT, 230

_AT, 204

_AT, 22

15_AT, 155

14_A_AT, 20

00_S_AT, 20

04_AT, 1555

32_S_AT, 20

_AT, 2221

_I_AT, 22

7

_AT, 2

5_S_AT, 214211_AT, 2145

1_X_AT, 21

_

_AT,

5_AT, 20

_S_AT, 1405_I_AT, 201544_X_AT, 22

_AT, 2117

_X_AT, 22

01_AT, 20

_AT, 212

7_AT, 22

0_AT, 20

_S_AT, 1557

5_S_AT, 2

02_S_AT, 20

5_AT, 222

70_S_AT, 2

20_S_AT, 21

_S_AT, 2

_S_AT, 217

6_AT, 20

751_X_AT, 201150_S_AT, 2011

_S_AT, 155

2_AT, 217757_AT, 21

_AT, 1545734_X_AT, 22

_AT, 20

_AT, 211

4_S_AT, 22

2_AT, 22

_AT, 21

0_S_AT, 2020

_AT, 23

_AT, 15

5752_AT, 20

_AT, 204

_S_AT, 370

_AT, 2

5

_S_AT, 225557_AT, 237

1_AT, 37152_AT, 22

_AT, 2427

_AT,

_AT, 20

0

_S_AT, 20

3_AT, 20

_S_AT, 21

42_S_AT, 22517

_AT, 22

6_AT, 200

78_AT, 225366_AT, 202

_AT, 2

3665_AT, 2047

6_S_AT, 20

1_AT, 20

_X_AT, 23

519_AT, 20

_X_AT, 21

3

_AT, 22

11

_AT, 2121

0_AT, 20

71

_AT, 22

_S_AT, 201

_S_AT, 212143_S_AT, 215

02_AT, 22

_AT, 2

_S_AT, 20

7_S_AT, 2276

1_S_AT, 202

_S_AT, 21

_AT, 24

7

7_AT, 2273

0_AT, 210427_X_AT, 22

_AT, 21

_S_AT, 2007

_S_AT, 204401_AT,

0

_S_AT, 222062_AT, 21

45_AT, 2272

_AT, 21

_AT, 210522_S_AT, 22

1

_AT, 217

2_X_AT, 2

525_X_AT, 2020

1_AT, 2

1

_AT, 20

0_AT, 20

02_S_AT, 22

4_S_AT, 2424

_AT, 202241_AT, 2

1044_X_AT, 220

13_AT, 2

_AT, 210

_AT, 1

1_A_AT, 20

5_AT, 21

1_AT, 215

_AT, 20

0

_AT, 210

5_X_AT, 22

221_AT, 210

6_AT, 20

5_S_AT, 23

15

_AT, 222041_S_AT, 201473_AT,

_AT, 21

1

_S_AT, 2113

2_S_AT, 1

17_AT, 201471_S_AT, 2

57

_AT, 204472_S_AT, 20

2_AT, 22

_S_AT, 2244

0_S_AT, 202

_S_AT, 21425

_AT, 2022

4_S_AT, 23

1_AT, 20

27_S_AT, 20

5_S_AT, 15

_AT, 22

0_AT, 207

10_S_AT, 20

_AT, 212

_AT, 20

7

_AT, 155

1_A_AT, 225215_AT, 212477_AT, 20

0

_AT, 20

22_AT, 220

25_AT, 210

5_S_AT, 24

6_AT, 201005_AT, 20

3_S_AT, 2

220_AT, 215292_S_AT, 1500

_AT, 212171_X_AT, 2142

7_AT,

402_AT, 2

2

_AT, 2

4

7_AT, 224

_AT, 2

0

_AT, 202191_S_AT, 223

_AT, 202

_AT, 2

1

_X_AT, 223

_AT, 20

_S_AT, 20

04_AT, 2027

_AT, 22

0

_AT, 220

1

_S_AT, 215

_AT, 23

1_AT, 200

72_AT, 212

_AT, 22

7_AT, 22

7_S_AT, 21

4_AT, 212

0

_AT, 217279_X_AT, 221841_S_AT, 2

_AT, 2

34_S_AT, 23422

_S_AT, 212

_AT, 21

2_AT, 24

_AT, 204172_AT, 25

_AT, 15

01_AT, 25

_AT, 200

1

_AT, 203

_AT, 204

0_S_AT, 20

_S_AT, 2033

_S_AT, 2

30_AT, 20

157_AT, 225

7_AT, 20

015_AT, 232224_AT, 225

_AT, 24177

_AT, 2

2_AT, 22

50_AT, 2010

2_AT, 20

3_AT, 212

_

_AT, 2

4442_X_AT, 21

_X_AT, 20

22_X_AT, 2

1722_X_AT, 22

708_AT, 22

_S_AT, 227107_AT, 211

2_X_AT, 20

0_S_AT, 20

S_AT, 225207_AT, 20

21_S_AT,

0

_S_AT, 2230

2_AT, 202

7_S_AT, 205419_AT,

7300_AT, 1562

7_AT, 210

_S_AT, 20

71_S_AT, 22

_AT, 22470

_AT, 220

5_S_AT, 20

_AT, 15525

_A_AT, 20

_AT, 21

4_AT, 20

097_S_AT, 21237

_AT, 217

_X_AT, 227

7_AT, 15

5258_X_AT, 241

_AT, 21

4

4_AT, 2

_AT, 22

_AT GOTERM_(—) 39402_AT, 217757_AT, 216243_S_AT, 1405_I_AT, 204655_AT,2091

9_AT, 201473_AT, 201044_X_AT, BP_ALL 201041_S_AT, 23

669_AT, 212657_S_AT, 205067_AT, 202284_S_AT, 1555759_A_AT, 207

19_S_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 229221_AT, 212171_X_AT,39402_AT, 1405_I_AT, 201566_X_AT, BP_ALL 212014_X_AT, 226218_AT,223501_AT, 210916_S_AT, 218559_S_AT, 204923_AT, 1557905_S_AT, 222067_AT,205067_AT, 210512_S_AT, 202284_S_AT, 222670_S_AT, 217552_X_AT,220066_AT, 211527_X_AT, 201925_S_AT, 209906_AT, 204489_S_AT, 203665_AT,205

91_AT, 203140_AT, 204490_S_AT, 227752_AT, 213281_AT, 204655_AT,210513_S_AT, 201565_S_AT, 209635_X_AT, 221502_S_AT, 201466_S_AT,1552914_A_AT, 203233_AT, 205312_AT, 1555759_A_AT, 224859_AT GOTERM_(—)39402_AT, 217757_AT, 216243_S_AT, 1405_I_AT, 204655_AT, 2091

9_AT, 201473_AT, 201044_X_AT, BP_ALL 201041_S_AT, 23

669_AT, 212657_S_AT, 205067_AT, 2022

4_S_AT, 1555759_A_AT, 207

19_S_AT GOTERM_(—) 202540_S_AT, 2014

4_X_AT, 201465_S_AT, 21

02

_AT, 216248_S_AT, 39402_AT, 204622_X_AT, BP_ALL 205463_S_AT, 1405_I_AT,211924_S_AT, 214

_AT, 223877_AT, 229830_AT, 205059_S_AT, 211

61_X_AT, 235739_AT, 213763_AT, 2050

7_AT, 202

59_X_AT, 223092_AT, 221463_AT, 209827_S_AT, 210839_S_AT, 1554992_AT, 20

06_AT, 20276

_AT, 2132

1_AT, 204655_AT, 20

1

5_AT, 225116_AT, 201466_S_AT, 204025_AT, 225115_AT, 2204

4_AT, 2250

7_AT, 225797_AT, 2253

_AT, 1555759_A_AT, 209

2_AT, 210815_S_AT, 2156

_AT, 202539_S_AT, 2050

_AT GOTERM_(—) 201464_X_AT, 237252_AT, 201463_S_AT, 39402_AT, 202241_AT,2132

1_AT, 1405_I_AT, 204655_AT, BP_ALL 1552553_A_AT, 20

9_AT, 202708_S_AT, 201466_S_AT, 203

_AT, 221661_X_AT, 222062_AT, 219

1

_X_AT, 203

7_S_AT, 227697_AT, 205495_S_AT, 205067_AT, 1555759_A_AT, 2200

6_AT, 206438_S_AT GOTERM_(—) 219028_AT, 216248_S_AT, 39402_AT,205463_S_AT, 204622_X_AT, 1405_I_AT, 211924_S_AT, BP_ALL 214866_AT,222877_AT, 229830_AT, 205099_S_AT, 211661_X_AT, 235739_AT, 213763_AT,205067_AT, 202859_X_AT, 223092_AT, 22

63_AT, 209827_S_AT, 210

39_S_AT, 20

06_AT, 20

655_AT, 225116_AT, 204035_AT, 225115_AT, 2204

4_AT, 225097_AT, 229797_AT, 2253

_AT, 1555759_A_AT, 20

392_AT, 210

45_S_AT, 205098_AT, GOTERM_(—) 201464_X_AT, 213891_S_AT, 201465_S_AT,227069_AT, 21902

_AT, 21229

_AT, 210136_AT, BP_ALL 216834_AT, 201471_S_AT, 235739_AT, 202

2

_S_AT, 201067_AT, 236561_AT, 202

59_X_AT, 2022

4_S_AT, 201170_S_AT, 203729_AT, 2284

0_AT, 21

017_S_AT, 2120

_AT, 201247_S_AT, 201565_S_AT, 20

753_AT, 221

15_AT, 2552914_A_AT, 225215_AT, 22214

_S_AT, 205312_AT, 201005_AT, 2100

5_S_AT, 160020_AT, 214211_AT, 212171_X_AT, 21624

_S_AT, 63

25_AT, 39402_AT, 205

63_S_AT, 201566_X_AT, 22

964_AT, 22

501_AT, 22339

_AT, 22

30_AT, 212387_AT, 205566_AT, 21

502_S_AT, 239

1

_X_AT, 222670_S_AT, 208476_S_AT, 200920_S_AT, 201150_S_AT, 201148_S_AT,217757_AT, 20276

_AT, 2132

1_AT, 210513_S_AT, 23

9_AT, 203233_AT, 2

451_AT, 2123

6_AT, 225097_AT, 219257_S_AT, 212

3_AT, 2175

1_AT, 217279_X_AT, 37152_AT, 221

41_S_AT, 224218_S_AT, 213763_AT, 1566901_AT, 220066_AT, 202

_AT, 203665_AT, 204

_S_AT, 201149_S_AT, 239519_AT, 225116_AT, 22

502_S_AT, 201466_S_AT, 225337_AT, 212143_S_AT, 204035_AT, 225368_AT, 202

_S_AT, 20

7_S_AT, 222652_S_AT, 224859_AT, 205681_AT, 201012_AT, 204622_X_AT,241722_X_AT, 218559_S_AT, 200748_S_AT, 203940_S_AT, 200

21_S_AT, 219

45_AT, 21990

_AT, 210512_S_AT, 202

27_S_AT,

7100_AT, 211527_X_AT, 20

140_AT, 220266_S_AT, 202241_AT, 2039

5_AT, 21025

_AT, 2276

7_AT, 2263

2_AT, 2233

_AT GOTERM_(—) 160020_AT, 217173_S_AT, 20114

_S_AT, 203

5_AT, 39402_AT, 205463_S_AT, 201149_S_AT, BP_ALL 201147_S_AT, 20206

_S_AT, 201044_X_AT, 229

30_AT, 201042_S_AT, 201313_AT, 227697_AT, 202

2

_S_AT, 205067_AT, 202827_S_AT, 236561_AT, 209047_AT, 217279_X_AT, 2020

7_S_AT, 201150_S_AT GOTERM_(—) 2

1464_X_AT, 214211_AT, 201465_S_AT, 225723_AT, 37152_AT, 210136_AT,212171_X_AT, BP_ALL 39402_AT, 1405_I_AT, 241938_AT, 34210_AT, 20

61_AT, 205099_S_AT, 20074

_S_AT, 20

54

_S_AT, 205067_AT, 210512_S_AT, 211527_X_AT, 200

7

_AT, 201925_S_AT, 1562

67_AT, 217173_S_AT, 209906_AT, 216017_S_AT, 2036

5_AT, 2132

1_AT, 204655_AT, 210513_S_AT, 20206

_S_AT, 20

466_S_AT, 239452_AT, 15565

3_A_AT, 212

03_AT, 1555759_A_AT, 241773_AT, 201005_AT,

GOTERM_(—) 204912_AT, 213428_S_AT, 20

555_S_AT, 217757_AT, 205463_S_AT, 210233_AT, 226218_AT, MF_ALL229830_AT, 212143_S_AT, 200935_AT, 203233_AT, 206

_S_AT, 228766_AT, 23

61_AT, 241929_AT, 210095_S_AT GOTERM_(—) 160020_AT, 20

665_AT, 201069_AT, 21624

_S_AT, 212171_X_AT, 204527_X_AT, 205463_S_AT, BP_ALL 210513_S_AT, 229

30_AT, 235739_AT, 219451_AT, 2276

7_AT, 15565

3_A_AT, 202

2

_S_AT, 210512_S_AT, 2022

4_S_AT, 202

27_S_AT, 236562_AT, 211527_X_AT, 217179_X_AT, 201242_S_AT, 200

7

_AT, 201243_S_AT GOTERM_(—) 202540_S_AT, 20

55_S_AT, 205

52_S_AT, 2024

5_S_AT, 204972_AT, 2110

6_X_AT, 222

77_AT, CC_ALL 216971_

_AT, 20

079_X_AT, 219412_AT, 202434_S_AT, 2064

_S_AT, 24155

_AT, 20

_AT, 201925_S_AT, 20

5_AT, 202436_S_AT, 20

91_AT, 2120

_AT, 216080_S_AT, 201500_X_AT, 2

8161_S_AT, 211577_AT, 22

502_S_AT, 236345_AT, 212

6_X_AT, 21

562_S_AT, 22

7

_AT, 20550

_AT, 2060

_S_AT, 20

9

_AT, 202

19_S_AT, 201324_AT, 202539_S_AT, 213503_X_AT, 224

67_AT, 1405_I_AT, 21

427_X_AT, 223501_AT, 2040

_AT, 204

1_AT,

4210_AT, 20

_S_AT, 2

95_S_AT, 215

6_S_AT, 205212_X_AT, 1562467_AT, 1554952_AT, 20921

_AT, 20

892_S_AT, 204059_S_AT, 2045

5_AT, 2091

_AT, 202437_S_AT, 1554

00_S_AT, 2

_AT, 204257_AT, 20131

_AT, 212089_AT, 2394

_AT, 20

81_S_AT, 155

5

3_A_AT, 202087_S_AT, 21925

_S_AT, 1555799_A_AT, 226302_AT, 203411_S_AT, 141929_AT, 2136

_AT GOTERM_(—) 202540_S_AT, 209555_S_AT, 202435_S_AT, 205552_S_AT,204972_AT, 211066_X_AT, 222877_AT, CC_ALL 216971_S_AT, 209079_X_AT,219412_AT, 202434_S_AT, 206488_S_AT, 241954_AT, 203939_AT, 203665_AT,202436_S_AT, 212099_AT, 216080_S_AT, 208161_S_AT, 213577_AT, 236345_AT212086_X_AT, 213562_S_AT, 228766_AT, 203508_AT, 206033_S_AT, 209993_AT,201324_AT 207819_S_AT, 202539_S_AT, 224967_AT, 34210_AT, 204661_AT,209994_S_AT, 215836_S_AT 205717_X_AT, 1562467_AT, 1554992_AT, 209218_AT,209189_AT, 202437_S_AT, 1554600_S_AT 238669_AT, 204257_AT, 212089_AT,201313_AT, 239451_AT, 204881_S_AT, 1556583_A_AT, 219257_S_AT,203411_S_AT, 226302_AT, 241929_AT, 215688_AT GOTERM_(—) 209906_AT,39402_AT, 205463_S_AT, 1405_I_AT, 204655_AT, 211924_S_AT, 214866_AT,222877_AT, BP_ALL 229830_AT, 205099_S_AT, 211661_X_AT, 204035_AT,205067_AT, 202859_X_AT, 1555759_A_AT, 209392_AT, 210845_S_AT, 221463_AT,209827_S_AT, 210839_S_AT, 205098_AT GOTERM_(—) 209906_AT, 39402_AT,205463_S_AT, 1405_I_AT, 204655_AT, 211924_S_AT, 214866_AT, 222877_AT,BP_ALL 229830_AT, 205099_S_AT, 211661_X_AT, 204035_AT, 205067_AT,202859_X_AT, 1555759_A_AT, 209392_AT, 210845_S_AT, 221463_AT,209827_S_AT, 210839_S_AT, 205098_AT GOTERM_(—) 219028_AT, 39402_AT,216834_AT, 223398_AT, 213763_AT, 239819_X_AT, 219645_AT, 205067_AT,BP_ALL 1566901_AT, 219908_AT, 220066_AT, 202388_AT, 203140_AT,202241_AT, 225116_AT, 212143_S_AT, 203935_AT, 225115_AT, 21025

_AT, 227697_AT, 225097_AT, 202988_S_AT, 225368_AT, 217591_AT,210095_S_AT GOTERM_(—) 201464_X_AT, 229221_AT, 201465_S_AT, 39402_AT,212014_X_AT, 201473_AT, 210916_S_AT, BP_ALL 1557905_S_AT, 205067_AT,236561_AT, 202284_S_AT, 201150_S_AT, 201148_S_AT, 204489_S_AT,203665_AT, 204490_S_AT, 2132

1_AT, 201149_S_AT, 201147_S_AT, 209189_AT, 209835_X_AT, 201466_S_AT,201313_AT, 227697_AT, 209122_AT GOTERM_(—) 201464_X_AT, 201465_S_AT,219028_AT, 212298_AT, 219155_AT, 209555_S_AT, 216834_AT, BP_ALL211352_S_AT, 219412_AT, 201471_S_AT, 235739_AT, 206472_S_AT,208960_S_AT, 226389_S_AT, 205067_AT, 236561_AT, 202859_X_AT, 20

891_AT, 207610_S_AT, 225171_AT, 212099_AT, 220307_AT, 230266_AT,1553982_A_AT, 207700_S_AT, 203104_AT, 225115_AT, 212977_AT,1555832_S_AT, 228766_AT, 204834_AT, 210845_S_AT, 230925_AT, 20

961_S_AT, 214581_X_AT, 214297_AT, 216248_S_AT, 39402_AT, 210233_AT,1405_I_AT, 214866_AT, 238909_AT, 223501_AT, 2020

6_AT, 205039_S_AT, 239818_X_AT, 221463_AT, 209906_AT, 1554992_AT,213281_AT, 224606_AT, 211676_S_AT, 225738_AT, 216250_S_AT, 202073_AT,203233_AT, 200872_AT, 225097_AT, 219257_S_AT, 219994_AT, 227948_AT,238649_AT, 211924_S_AT, 201041_S_AT, 206488_S_AT, 213763_AT, 206171_AT,225173_AT, 220066_AT, 200878_AT, 225166_AT, 204736_S_AT, 205891_AT,203665_AT, 239519_AT, 218856_AT, 225116_AT, 201466_S_AT, 223502_S_AT,204035_AT, 223939_AT, 225368_AT, 202988_S_AT, 241773_AT, 201012_AT,218501_AT, 204622_X_AT, 243797_AT, 22

708_AT, 226218_AT, 211661_X_AT, 202686_S_AT, 20

93_S_AT, 225207_AT, 227265_AT, 2251

_AT, 205419_AT, 206571_S_AT, 22

368_AT, 20

92_S_AT, 202241_AT, 204655_AT, 2091

9_AT, 203037_S_AT, 214054_AT, 220313_AT, 201044_X_AT, 201595_AT,227697_AT, 1555759_A_AT, 241929_AT, 219434_AT, 215688_AT, 203320_AT,205098_AT GOTERM_(—) 212171_X_AT, 215026_AT, 39402_AT, 1405_I_AT,223501_AT, 204923_AT, 222062_AT, 213763_AT, BP_ALL 205067_AT,217552_X_AT, 202859_X_AT, 210512_S_AT, 208436_S_AT, 220066_AT,209827_S_AT, 211527_X_AT, 201925_S_AT, 209906_AT, 205891_AT, 204655_AT,210513_S_AT, 225116_AT, 223502_S_AT, 204035_AT, 225115_AT, 225097_AT,225368_AT, 1555759_A_AT GOTERM_(—) 160020_AT, 216248_S_AT, 39402_AT,204622_X_AT, 205463_S_AT, 216243_S_AT, 1405_I_AT, BP_ALL 201473_AT,204058_AT, 229630_AT, 201041_S_AT, 235739_AT, 212657_S_AT, 202828_S_AT,205067_AT, 202284_S_AT, 202827_S_AT, 236561_AT, 209047_AT, 1562467_AT,201150_S_AT, 217173_S_AT, 201148_S_AT, 203665_AT, 217757_AT,204059_S_AT, 204655_AT, 201149_S_AT, 2091

9_AT, 201147_S_AT, 202068_S_AT, 201044_X_AT, 238669_AT, 201313_AT,227697_AT, 1555759_A_AT, 217279_X_AT, 202067_S_AT, 207819_S_ATGOTERM_(—) 203665_AT, 205891_AT, 203940_S_AT, 39402_AT, 200921_S_AT,212099_AT, 219257_S_AT, BP_ALL 205067_AT, 208937_S_AT, 200920_S_ATGOTERM_(—) 201464_X_AT, 201465_S_AT, 229221_AT, 216248_S_AT, 39402_AT,204522_X_AT, 205463_S_AT, BP_ALL 221841_S_AT, 212014_X_AT, 210916_S_AT,229830_AT, 201041_S_AT, 235739_AT, 1557905_S_AT, 202686_S_AT, 205067_AT,202284_S_AT, 201150_S_AT, 201148_S_AT, 2044

9_S_AT, 203655_AT, 205891_AT, 204490_S_AT, 220266_S_AT, 217757_AT,213281_AT, 201149_S_AT, 209189_AT, 201147_S_AT, 209835_X_AT,201044_X_AT, 201466_S_AT, 227697_AT, 1556583_A_AT GOTERM_(—)201464_X_AT, 213891_S_AT, 229221_AT, 201465_S_AT, 219028_AT, 212298_AT,209555_S_AT, BP_ALL 212014_X_AT, 201473_AT, 211352_S_AT, 210916_S_AT,201471_S_AT, 235739_AT, 208960_S_AT, 205067_AT, 217997_AT, 236561_AT,202284_S_AT, 1569149_AT, 204489_S_AT, 201147_S_AT, 201565_S_AT,203753_AT, 207700_S_AT, 1552914_A_AT, 225115_AT, 1555832_S_AT,228766_AT, 222146_S_AT, 205312_AT, 243536_AT, 208961_S_AT, 210095_S_AT,212171_X_AT, 216248_S_AT, 39402_AT, 205463_S_AT, 1405_I_AT, 235457_AT,201566_X_AT, 223501_AT, 2296830_AT, 2123

7_AT, 2020

6_AT, 1557905_S_AT, 222670_S_AT, 200920_S_AT, 201150_S_AT, 203751_X_AT,217996_AT, 20114

_S_AT, 1554992_AT, 213281_AT, 224606_AT, 210513_S_AT, 1565754_X_AT,225842_AT, 235295_AT, 1565752_AT, 203233_AT, 204105_S_AT, 212386_AT,225097_AT, 203752_S_AT, 219257_S_AT, 225557_AT, 37152_AT, 227948_AT,221841_S_AT, 242794_AT, 21294

_AT, 204923_AT, 201041_S_AT, 206488_S_AT, 213763_AT, 1554453_AT,1566901_AT, 220066_AT, 200878_AT, 205891_AT, 203665_AT, 204490_S_AT,201149_S_AT, 239519_AT, 209835_X_AT, 225116_AT, 204715_AT, 206157_AT,201466_S_AT, 223502_S_AT, 212143_S_AT, 204035_AT, 215602_AT, 212124_AT,225368_AT, 241773_AT, 224859_AT, 218501_AT, 243797_AT, 204622_X_AT,227240_AT, 226218_AT, 218559_S_AT, 227107_AT, 204401_AT, 200921_S_AT,203548_S_AT, 210512_S_AT, 211527_X_AT, 244414_AT, 203140_AT, 242405_AT,220266_S_AT, 204655_AT, 1552553_A_AT, 209189_AT, 201044_X_AT, 203935_AT,227697_AT, 1555759_A_AT, 241929_AT, 21563

_AT, 223394_AT GOTERM_(—) 202540_S_AT, 209555_S_AT, 202435_S_AT,205552_S_AT, 204972_AT, 211066_X_AT, 222877_AT, CC_ALL 209079_X_AT,219412_AT, 202434_S_AT, 206488_S_AT, 241954_AT, 203939_AT, 203665_AT,202436_S_AT, 212099_AT, 216080_S_AT, 208161_S_AT, 213577_AT, 236345_AT,213562_S_AT, 228766_AT, 203508_AT, 206033_S_AT, 201324_AT, 207819_S_AT,209993_AT, 202539_S_AT, 224967_AT, 34210_AT, 204661_AT, 209994_S_AT,215836_S_AT, 205717_X_AT, 1562467_AT, 1554992_AT, 209218_AT, 209189_AT,202437_S_AT, 238669_AT, 204257_AT, 201313_AT, 239451_AT, 204881_S_AT,1556583_A_AT, 219257_S_AT, 226302_AT, 241929_AT, 215688_AT GOTERM_(—)202540_S_AT, 223723_AT, 227069_AT, 212298_AT, 212014_X_AT, 221731_X_AT,203923_S_AT, 219412_AT, CC_ALL 207674_AT, 2186

1_AT, 209803_S_AT, 226545_AT, 203729_AT, 217173_S_AT, 2044

9_S_AT, 205505_AT, 204620_S_AT, 220307_AT, 223303_AT, 211307_S_AT,216080_S_AT, 232649_AT, 203922_S_AT, 21

6

6_S_AT, 221

15_AT, 1552

14_A_AT, 203104_AT, 2135

2_S_AT, 202756_S_AT, 22

766_AT, 224674_AT, 2145

1_X_AT, 224967_AT, 63825_AT, 211719_X_AT, 209949_AT, 223501_AT,205099_S_AT, 1557

05_S_AT, 215836_S_AT, 238542_AT, 209670_AT, 209047_AT, 240076_AT,217078_S_AT, 221

40_AT, 201626_AT, 219926_AT, 211676_S_AT, 238669_AT, 204257_AT,203233_AT, 204105_S_AT, 224989_AT, 239761_AT, 201263_S_AT, 204912_AT,23861

_AT, 222877_AT, 209079_X_AT, 212062_AT, 22

0

3_AT, 202434_S_AT, 204222_S_AT, 2064

_S_AT, 22

640_AT, 205542_AT, 203665_AT, 204736_S_AT, 205

1_AT, 204359_AT, 202748_AT, 239519_AT, 20

35_X_AT, 20

262_S_AT, 218

56_AT, 204715_AT, 223502_S_AT, 236345_AT, 223939_AT, 203

7_S_AT, 204774_AT, 20253

_S_AT, 22621

_AT, 204661_AT, 225

09_AT, 204401_AT, 202

_S_AT, 222062_AT, 2251

_AT, 217552_X_AT, 202071_AT, 2249

0_AT, 225325_AT, 220313_AT, 20571

_AT, 203

35_AT, 1556583_A_AT, 201995_AT, 229797_AT, 226302_AT, 210173_AT, 2050

8_AT, 210495_X_AT, 229221_AT, 210136_AT, 209555_S_AT, 202435_S_AT,211066_X_AT, 210916_S_AT, 2244

0_S_AT, 21

225_AT, 20282

_S_AT, 242

71_AT, 214255_AT, 236561_AT, 230360_AT, 201925_S_AT, 22

0_AT, 207610_S_AT, 212099_AT, 213577_AT, 229

37_X_AT, 214

30_AT, 227052_AT, 212977_AT, 20350

_AT, 2

0925_AT, 210

5_S_AT, 2010

5_AT, 206033_S_AT, 201242_S_AT, 233220_AT, 207819_S_AT, 242907_AT,209122_AT, 160020_AT, 237252_AT, 214297_AT, 210233_AT, 22

910_AT, 214

66_AT, 205534_AT, 34210_AT, 205566_AT, 209994_S_AT, 1552690_A_AT, 22

754_AT, 217678_AT, 205717_X_AT, 2385

1_AT, 209906_AT, 209218_AT, 215646_S_AT, 204619_S_AT, 205520_AT,213030_S_AT, 20

121_S_AT, 235295_AT, 20

1_S_AT, 239451_AT, 219994_AT, 217279_X_AT, 201125_S_AT, 202627_S_AT,231924_S_AT, 203217_S_AT, 206171_AT, 241554_AT, 203

3

_AT, 2

54_AT, 202436_S_AT, 204490_S_AT, 219386_S_AT, 20

921_AT, 225337_AT, 2204

4_AT, 209145_AT, 241773_AT, 22

762_AT, 20

392_AT, 224859_AT, 201625_S_AT, 201324_AT, 209993_AT, 201012_AT,212464_S_AT, 216442_X_AT, 227180_AT, 241722_X_AT, 22

708_AT, 214724_AT, 227107_AT, 211661_X_AT, 226

31_AT, 20354

_S_AT, 2193

5_AT, 202827_S_AT, 2230

2_AT,

7200_AT, 205419_AT, 210

39_S_AT, 235299_AT, 219332_AT, 202437_S_AT, 20206

_S_AT, 20

_AT, 223798_AT, 22

696_AT, 241929_AT, 202067_S_AT, 219434_AT, 211571_S_AT GOTERM_(—)160020_AT, 203665_AT, 201069_AT, 216248_S_AT, 212171_X_AT, 204622_X_AT,205463_S_AT, BP_ALL 220513_S_AT, 229

30_AT, 235739_AT, 23

451_AT, 15565

3_A_AT, 227697_AT, 202

2

_S_AT, 202827_S_AT, 210512_S_AT, 236561_AT, 217279_X_AT, 211527_X_AT,201242_S_AT, 2

78_AT, 201243_S_AT GOTERM_(—) 20

06_AT, 20

5_AT, 20

140_AT, 205

1_AT, 39402_AT, 217757_AT, 22621

_AT, 223501_AT, BP_ALL 223502_S_AT, 1552

14_A_AT, 204923_AT, 203233_AT, 222062_AT, 205067_AT, 217552_X_AT,220066_AT, 224

59_AT, 201925_S_AT GOTERM_(—) 219028_AT, 39402_AT, 216

34_AT, 22

8_AT, 213

63_AT, 239

1

_X_AT, 219

45_AT, 2050

7_AT, BP_ALL 15

01_AT, 21

0

_AT, 220066_AT, 202

_AT, 20

140_AT, 202241_AT, 22511

_AT, 21214

_S_AT, 2039

5_AT, 225115_AT, 21025

_AT, 227697_AT, 2250

7_AT, 2029

_S_AT, 22536

_AT, 2175

1_AT, 2100

5_S_AT GOTERM_(—) 203140_AT, 222062_AT, 227

97_AT, 39402_AT, 217757_AT, 20350

_AT, 205067_AT, 22621

_AT, BP_ALL 224

_AT, 20

9_AT, 233220_AT, 1552914_A_AT GOTERM_(—) 20114

_S_AT, 204620_S_AT, 20114

_S_AT, 221924_S_AT, 201147_S_AT, 215646_S_AT, 204619_S_AT, BP_ALL221731_X_AT, 214

6_AT, 20

6_S_AT, 227

7_AT, 2022

4_S_AT, 236561_AT, 210

45_S_AT, 211571_S_AT, 201150_S_AT, 20

5_S_AT GOTERM_(—) 160020_AT, 39402_AT, 205

3_S_AT, 2162

3_S_AT, 1405_I_AT, 20147

_AT, 204

5

_AT, 22

30_AT, BP_ALL 201041_S_AT, 212657_S_AT, 202

2

_S_AT, 205067_AT, 2022

4_S_AT, 202

27_S_AT, 236561_AT, 209047_AT, 201150_S_AT, 217173_S_AT, 2011

_S_AT, 203665_AT, 217757_AT, 204059_S_AT, 204

55_AT, 2011

_S_AT, 2091

_AT, 201147_S_AT, 20206

_S_AT, 2010

4_X_AT, 23

_AT, 201313_AT, 227

7_AT, 155575

_A_AT, 217279_X_AT, 202067_S_AT, 207

19_S_AT GOTERM_(—) 214211_AT, 201464_X_AT, 223723_AT, 2014

5_S_AT, 37152_AT, 2101

6_AT,

402_AT, 1

5_I_AT, BP_ALL 242938_AT, 20

661_AT, 34220_AT, 2050

9_S_AT, 2007

_S_AT, 205067_AT, 201925_S_AT, 1562467_AT, 20

06_AT, 216017_S_AT, 203

5_AT, 213281_AT, 204655_AT, 201

_S_AT, 239451_AT, 155

3_A_AT, 212

_AT, 155575

_A_AT, 241773_AT, 201005_AT, 2050

_AT GOTERM_(—) 210

5_X_AT, 22

221_AT, 37152_AT, 21229

_AT, 2

555_S_AT, 212014_S_AT, 221731_X_AT, BP_ALL 2110

_X_AT, 222877_AT, 210

_S_AT, 209079_X_AT, 2064

_S_AT, 228640_AT, 2044

_S_AT, 21342

_S_AT, 20

35

_AT, 2044

0_S_AT, 204620_S_AT, 2120

_AT, 22

_AT, 23

519_AT, 20

15_X_AT, 207571_X_AT, 22

7

_AT, 22

73_AT, 206013_S_AT, 201005_AT, 212464_S_AT, 216442_X_AT, 1405_I_AT,21171

_X_AT, 205534_AT, 2050

9_S_AT, 15579

5_S_AT, 215

36_S_AT, 205717_X_AT, 2251

_AT, 21707

_S_AT, 204655_AT, 215646_S_AT, 20

619_S_AT, 2107

5_S_AT, 20

037_S_AT, 216250_S_AT, 20

71

_AT, 2

41

5_S_AT, 155575

_A_AT, 241929_A_AT, 201125_S_AT, 211571_S_AT, 2050

_AT GOTERM_(—) 2104

5_X_AT, 229211_AT, 37152_AT, 2122

_AT, 20

555_S_AT, 212014_X_AT, 221731_X_AT, BP_ALL 212066_X_AT, 222

77_AT, 210916_S_AT, 2

9079_X_AT, 206

_S_AT, 22

640_AT, 2044

_S_AT; 21342

_S_AT, 20435

_AT, 20

490_S_AT, 204620_S_AT, 2120

_AT, 223

03_AT, 239519_AT, 20

35_X_AT, 207571_X_AT, 228766_AT, 22887

_AT, 206013_S_AT, 201005_AT, 212464_S_AT, 216442_X_AT, 1405_I_AT,211719_X_AT, 205534_AT, 2050

9_S_AT, 1557

05_S_AT, 215

36_S_AT, 205717_X_AT, 22

1

_AT, 217070_S_AT, 2

4

55_AT, 2156

_S_AT, 204

19_S_AT, 210785_S_AT, 203037_S_AT, 216250_S_AT, 20571

_AT, 204105_S_AT, 155575

_A_AT, 24192

_AT, 201125_S_AT, 211571_S_AT, 2050

_AT GOTERM_(—) 214211_AT, 201

64_X_AT, 22

723_AT, 2014

_S_AT, 37152_AT, 210

6_AT, 39402_AT, 1405_I_AT, BP_ALL 241

_AT, 204661_AT, 34210_AT, 2050

_S_AT, 2007

_S_AT, 205067_AT, 201

25_S_AT, 1562

67_AT, 20

906_AT, 21

017_S_AT, 2132

1_AT, 2

655_AT, 20146

_S_AT, 23

452_AT, 155

_A_AT, 212

_AT, 155575

_A_AT, 2417

_AT, 20100

_AT, 2

0

_AT GOTERM_(—) 214231_AT, 201464_X_AT, 223723_AT, 201465_S_AT, 37152_AT,210136_AT, 39402_AT, 1405_I_AT BP_ALL 241938_AT, 204661_AT, 34210_AT,205099_S_AT, 200748_S_AT, 205067_AT, 201925_S_AT, 1562467_AT 209906_AT,216017_S_AT, 213281_AT, 204655_AT, 201466_S_AT, 239451_AT, 1556583_A_AT212803_AT, 1555759_A_AT, 241773_AT, 201005_AT, 205098_AT GOTERM_(—)209906_AT, 205891_AT, 203140_AT, 212171_X_AT, 39402_AT, 210513_S_AT,226218_AT, 223501_AT BP_ALL 223502_S_AT, 1552914_A_AT, 204923_AT,203233_AT, 222062_AT, 205067_AT, 210512_S_AT 202284_S_AT, 217552_X_AT,220066_AT, 211527_X_AT, 224859_AT, 201925_S_AT GOTERM_(—) 203665_AT,205891_AT, 203140_AT, 222062_AT, 39402_AT, 205067_AT, 220066_AT,226218_AT BP_ALL 204923_AT GOTERM_(—) 237252_AT, 201464_X_AT,201465_S_AT, 39402_AT, 202241_AT, 213281_AT, 1405_I_AT, 204655_AT BP_ALL209189_AT, 201466_S_AT, 203888_AT, 211661_X_AT, 239818_X_AT,203887_S_AT, 227697_AT 205067_AT, 1555759_A_AT, 220066_AT KEGG_(—)229221_AT, 204489_S_AT, 204490_S_AT, 209555_S_AT, 39402_AT, 212014_X_AT,209835_X_AT PATHWAY 226218_AT, 210916_S_AT, 203104_AT, 1557905_S_AT,203233_AT, 206488_S_AT, 228766_AT, 205067_AT 217552_X_AT, 241929_AT,201005_AT, 201925_S_AT GOTERM_(—) 203140_AT, 203233_AT, 222062_AT,39402_AT, 205067_AT, 220066_AT, 226218_AT, 223501_AT BP_ALL 223502_S_AT,204923_AT GOTERM_(—) 201464_X_AT, 237252_AT, 201465_S_AT, 37152_AT,219028_AT, 39402_AT, 1405_I_AT, 201473_AT BP_ALL 202708_S_AT, 202086_AT,211661_X_AT, 213763_AT, 203882_AT, 222062_AT, 239818_X_AT, 205067_AT,236561_AT, 208436_S_AT, 220066_AT, 209827_S_AT, 204475_AT, 217173_S_AT,214453_S_AT, 213281_AT, 202241_AT, 204655_AT, 1552553_A_AT, 209189_AT,202068_S_AT, 211676_S_AT, 225116_AT, 229937_X_AT, 201466_S_AT,206157_AT, 203888_AT, 225115_AT, 212977_AT, 203887_S_AT, 227697_AT,225097_AT, 205495_S_AT, 225368_AT, 1555759_A_AT, 202067_S_AT,208438_S_AT, 213293_S_AT GOTERM_(—) 201464_X_AT, 202540_S_AT,201465_S_AT, 37152_AT, 210136_AT, 202435_S_AT, 241938_AT, 212948_AT,BP_ALL 228083_AT, 202434_S_AT, 205067_AT, 200878_AT, 217173_S_AT,216017_S_AT, 205891_AT, 203665_AT, 202436_S_AT, 201149_S_AT,201147_S_AT, 201466_S_AT, 220484_AT, 201005_AT, 233220_AT, 202539_S_AT,212171_X_AT, 39402_AT, 204401_AT, 1552690_A_AT, 206835_AT, 204684_AT,235944_AT, 210512_S_AT, 209047_AT, 211527_X_AT, 201150_S_AT, 1562467_AT,201148_S_AT, 1554992_AT, 209906_AT, 213281_AT, 202437_S_AT, 209189_AT,210513_S_AT, 2020268_S_AT, 212372_AT, 238669_AT, 1556583_A_AT,229797_AT, 212803_AT, 202067_S_AT, 215688_AT GOTERM_(—) 213

1_S_AT, 201464_X_AT, 2025

0_S_AT, 2270

_AT, 2014

5_S_AT, 219028_AT, 21229

_AT, 212014_X_AT, BP_ALL 216

34_AT, 219412_AT, 20

60_S_AT, 217

93_AT, 205067_AT, 202

59_X_AT, 202170_S_AT, 20

729_AT, 2044

_S_AT, 116017_S_AT, 225171_AT, 220

07_AT, 201565_S_AT, 201147_S_AT, 230266_AT, 204

3_AT, 221

15_AT, 207700_S_AT, 1552914_A_AT, 20

104_AT, 1555

2_S_AT, 204

34_AT, 2221

_S_AT, 22

76

_AT, 210095_S_AT, 214211_AT, 2145

1_X_AT, 21624

_S_AT, 63

25_AT, 203

63_S_AT, 1405_I_AT, 201566_X_AT, 22

964_AT, 211719_X_AT, 223501_AT, 2020

_AT, 212

7_AT, 220

0_AT, 2000

9_S_AT, 1557

05_S_AT, 21

502_S_AT, 222670_S_AT, 200920_S_AT, 2191

3_S_AT, 20

_S_AT, 217

6_AT, 203751_X_AT, 201150_S_AT, 2011

_S_AT, 155

2_AT, 217757_AT, 22

3_AT, 1565754_X_AT, 20

606_AT, 213676_S_AT, 225

2_AT, 22573

_AT, 216250_S_AT, 202073_AT, 23

6

_AT, 1565752_AT, 203233_AT, 204105_S_AT, 3702

_AT, 20

752_S_AT, 225557_AT, 2175

1_AT, 37152_AT, 227

_AT, 24279

_AT, 2419

_AT, 201041_S_AT, 204

23_AT, 20

8_S_AT, 2119

2_S_AT, 225173_AT, 220066_AT, 20067

_AT, 2251

_AT, 202

_AT, 203

_AT, 20473

_S_AT, 205

1_AT, 21

529_AT, 209

5_X_AT, 21

5

_AT, 225116_AT, 2121

0_AT, 204715_AT, 223502_S_AT, 201466_S_AT, 212143_S_AT, 215

02_AT, 223

_AT, 202

_S_AT, 20

17_S_AT, 222651_S_AT, 202

_S_AT, 21

502_AT, 2437

7_AT, 227340_AT, 22

213_AT, 20074

_S_AT, 204401_AT, 202

_S_AT, 222062_AT, 21

45_AT, 2272

5_AT, 21

0

_AT, 210512_S_AT, 2251

_AT, 211527_X_AT, 202072_AT, 244414_AT, 203140_AT, 20

2_S_AT, 2202

_S_AT, 242

0

_AT, 202241_AT, 201044_X_AT, 220

13_AT, 20

_AT, 220

_AT, 201

_AT, 226302_AT, 215

_AT, 2050

_AT, 210

5_X_AT, 229221_AT, 2101

6_AT, 20

_S_AT, 219155_AT, 221011_S_AT, 201473_AT, 20247

_AT, 210

36_S_AT, 211352_S_AT, 1555

27_AT, 201471_S_AT, 23573

_AT, 206472_S_AT, 203

7_AT, 22

9_S_AT, 2244

0_S_AT, 202

2

_S_AT, 214255_AT, 2022

4_S_AT, 236561_AT, 209

27_S_AT, 156

149_AT, 22

490_AT, 207

10_S_AT, 20

1_AT, 2120

_AT, 20

753_AT, 155

_A_AT, 225125_AT, 212

77_AT, 20550

_AT, 205312_AT, 230

25_AT, 210

45_S_AT, 24

556_AT, 201005_AT, 20

61_S_AT, 21529

_S_AT, 160020_AT, 212171_X_AT, 214297_AT, 39402_AT, 2102

_AT, 235457_AT, 214

66_AT, 23

0

_AT, 202191_S_AT, 2233

_AT, 20

6_AT, 23

1

_X_AT, 221

63_AT, 20

436_S_AT, 2027

06_AT, 20

_AT, 224606_AT, 210511_S_AT, 2352

5_AT, 23

451_AT, 200

72_AT, 2123

6_AT, 2250

7_AT, 219257_S_AT, 21

4_AT, 212

0

_AT, 217279_X_AT, 221841_S_AT, 23

49_AT, 211924_S_AT, 22421

_S_AT, 2129

_AT, 213763_AT, 206171_AT, 1564433_AT, 156

01_AT, 1560226_AT, 202014_AT, 2044

0_S_AT, 2049

_S_AT, 20114

_S_AT, 23

570_AT, 20

157_AT, 225

7_AT, 204235_AT, 212124_AT, 22536

_AT, 241773_AT, 20

292_AT, 224

59_AT, 201012_AT, 205681_AT, 212464_S_AT, 216442_X_AT, 204622_X_AT,241722_X_AT, 22

70

_AT, 21

559_S_AT, 227107_AT, 211

1_X_AT, 20

40_S_AT, 20

3_S_AT, 225207_AT, 200

21_S_AT, 203548_S_AT, 202

27_S_AT, 20541

_AT,

7100_AT, 1562467_AT, 210

_S_AT, 206571_S_AT, 22

36

_AT, 224701_AT, 220

35_S_AT, 204

_AT, 1552553_A_AT, 20

1

_AT, 214054_AT, 203037_S_AT, 212372_AT, 2276

7_AT, 155575

_A_AT, 241

29_AT, 21943

_AT, 20

20_AT, 22

_AT GOTERM_(—) 203140_AT, 203233_AT, 222062_AT, 39402_AT, 205067_AT,220066_AT, 226218_AT, 223501_AT, BP_ALL 223502_S_AT, 204923_ATGOTERM_(—) 223723_AT, 212099_AT, 228708_AT, 211924_S_AT, 214866_AT,34210_AT, 204661_AT, 202756_S_AT, CC_ALL 203548_S_AT, 238542_AT,226545_AT, 210

45_S_AT, 203939_AT, 201925_S_AT GOTERM_(—) 201464_X_AT, 214211_AT,201465_S_AT, 223723_AT, 37152_AT, 212171_X_AT, 210136_AT, BP_ALL39402_AT, 241722_X_AT, 1405_I_AT, 201566_X_AT, 22621

_AT, 223501_AT, 241938_AT, 204661_AT, 34210_AT, 20074

_S_AT, 205099_S_AT, 204401_AT, 2035

8_S_AT, 205067_AT, 210512_S_AT, 211527_X_AT, 20087

_AT, 201925_S_AT, 1562467_AT, 217173_S_AT, 209906_AT, 216017_S_AT,203665_AT, 203140_AT, 2132

1_AT, 204655_AT, 210513_S_AT, 201565_S_AT, 202068_S_AT, 223502_S_AT,201466_S_AT, 239451_AT, 15565

3_A_AT, 212803_AT, 1555759_A_AT, 241773_AT, 201005_AT, 202067_S_AT,20509

_AT GOTERM_(—) 206488_S_AT, 37152_AT, 209555_S_AT, 22

754_AT, 22

766_AT, 226302_AT, 211030_S_AT BP_ALL 205920_AT, 241929_AT, 208161_S_AT,201012_AT, 209122_AT GOTERM_(—) 212171_X_AT, 63825_AT, 205463_S_AT, 229

30_AT, 205566_AT, 203940_S_AT, 239

18_X_AT, BP_ALL 202859_X_AT, 210512_S_AT, 87100_AT, 209827_S_AT,211527_X_AT, 210

39_S_AT, 228490_AT, 203665_AT, 202241_AT, 210513_S_AT, 212190_AT,221815_AT, 225337_AT, 212143_S_AT, 204035_AT, 219257_S_AT, 209392_AT,210095_S_AT GOTERM_(—) 213

91_S_AT, 201464_X_AT, 227069_AT, 201465_S_AT, 37152_AT, 21902

_AT, 221

41_S_AT, BP_ALL 201473_AT, 242794_AT, 21294

_AT, 201471_S_AT, 235739_AT, 20

960_S_AT, 213763_AT, 1566901_AT, 200

7

_AT, 203665_AT, 2049

_S_AT, 201565_S_AT, 203753_AT, 204653_AT, 225116_AT, 201466_S_AT,225115_AT, 1555

32_S_AT; 222146_S_AT, 212124_AT, 22536

_AT, 205312_AT, 20

37_S_AT, 20

61_S_AT, 21624

_S_AT, 212171_X_AT, 204622_X_AT, 235457_AT, 201566_X_AT, 22

64_AT, 212387_AT, 218559_S_AT, 222670_S_AT, 210512_S_AT, 20

436_S_AT, 211527_X_AT, 203751_X_AT, 244414_AT, 203140_AT, 242405_AT,220266_S_AT, 20276

_AT, 2132

1_AT, 224606_AT, 209189_AT, 210513_S_AT, 212386_AT, 225097_AT,203752_S_AT, 225557_AT, 217591_AT GOTERM_(—) 213

91_S_AT, 201464_X_AT, 201465_S_AT, 219028_AT, 221

41_S_AT, 201473_AT, 242794_AT, BP_ALL 211352_S_AT, 212948_AT,201471_S_AT, 23573

_AT, 20

960_S_AT, 213763_AT, 205067_AT, 236561_AT, 220066_AT, 200

78_AT, 205

92_AT, 20

65_AT, 203753_AT, 225116_AT, 206157_AT, 201466_S_AT, 1552914_A_AT,207700_S_AT, 225115_AT, 1555

32_S_AT, 222146_S_AT, 212124_AT, 22536

_AT, 205312_AT, 20

961_S_AT, 224

59_AT, 21624

_S_AT, 212171_X_AT, 39402_AT 204622_X_AT, 205463_S_AT, 235457_AT, 2123

7_AT, 22

30_AT, 218559_S_AT, 222670_S_AT, 210512_S_AT, 211527_X_AT, 244414_AT,242405_AT, 220266_S_AT, 213281_AT, 224606_AT, 2091

9_AT, 210513_S_AT, 203

35_AT, 2123

6_AT, 225097_AT, 225557_AT, 223394_AT GOTERM_(—) 237252_AT, 213503_X_AT,209555_S_AT, 208816_X_AT, 210427_X_AT, 211924_S_AT, 201590_X_AT, BP_ALL214

66_AT, 203074_AT, 20

_AT, 204401_AT, 2054

_S_AT, 206

35_AT, 203

7_S_AT, 22

766_AT, 235944_AT, 241929_AT, 210845_S_AT, 201005_AT GOTERM_(—)217173_S_AT, 37152_AT, 20

555_S_AT, 39402_AT, 219155_AT, 238649_AT, 20206

_S_AT, BP_ALL 212062_AT, 204401_AT, 226390_AT, 206

_S_AT, 22

766_AT, 214255_AT, 205067_AT, 226302_AT, 241929_AT, 202067_S_AT,201012_AT, 209122_AT GOTERM_(—) 203665_AT, 203140_AT, 205

91_AT, 39402_AT, 205463_S_AT, 226218_AT, 223501_AT, 229

30_AT, BP_ALL 223502_S_AT, 204923_AT, 1552914_A_AT, 203233_AT,222062_AT, 205067_AT, 2022

_S_AT, 22

59_AT GOTERM_(—) 237252_AT, 201464_X_AT, 201465_S_AT, 39402_AT,202241_AT, 2132

3_AT, 1405_I_AT, 204655_AT, BP_ALL 20

189_AT, 201466_S_AT, 203

_AT, 211661_X_AT, 239

1

_X_AT, 203

7_S_AT, 2276

7_AT, 205067_AT, 1555759_A_AT, 220066_AT GOTERM_(—) 210495_X_AT, 2164

2_X_AT, 229221_AT, 212171_X_AT, 212014_X_AT, 211719_X_AT, 221731_X_AT,MF_ALL 210916_S_AT, 1557

05_S_AT, 201548_S_AT, 22

1

6_S_AT, 210512_S_AT, 220066_AT, 211527_X_AT, 210

39_S_AT, 2044

9_S_AT, 20

490_S_AT, 204620_S_AT, 215646_S_AT, 20

619_S_AT, 210513_S_AT, 209

35_X_AT, 212190_AT, 206157_AT, 209192_AT, 211571_S_AT, 212464_S_ATGOTERM_(—) 210495_X_AT, 216442_X_AT, 229221_AT, 212171_X_AT,212014_X_AT, 211719_X_AT, 221731_X_AT, MF_ALL 210916_S_AT, 1557905_S_AT,20354

_S_AT, 22

1

6_S_AT, 210512_S_AT, 220066_AT, 211527_X_AT, 210

39_S_AT, 2044

_S_AT, 204490_S_AT, 204620_S_AT, 215646_S_AT, 204619_S_AT, 210513_S_AT,20

35_X_AT, 212190_AT, 206157_AT, 209392_AT, 211571_S_AT, 212464_S_ATGOTERM_(—) 201464_X_AT, 201465_S_AT, 37152_AT, 212298_AT, 219028_AT,221841_S_AT, 204923_AT, BP_ALL 213763_AT, 205067_AT, 1566901_AT, 202

59_X_AT, 2022

4_S_AT, 236561_AT, 203729_AT, 203665_AT, 239519_AT, 201565_S_AT,225116_AT, 223502_S_AT, 201466_S_AT, 212143_S_AT, 1552914_A_AT,204035_AT, 225115_AT, 212124_AT, 225368_AT, 201005_AT, 224

59_AT, 210095_S_AT, 201012_AT, 214211_AT, 212171_X_AT, 39402_AT,205463_S_AT, 201566_X_AT, 223501_AT, 22

30_AT, 200748_S_AT, 239818_X_AT, 203940_S_AT, 200921_S_AT, 210512_S_AT,200920_S_AT, 211527_X_AT, 203140_AT, 220266_S_AT, 202241_AT, 213281_AT,210513_S_AT, 23

669_AT, 225097_AT, 219257_S_AT, 223394_AT GOTERM_(—) 213891_S_AT,201464_X_AT, 201465_S_AT, 219028_AT, 221841_S_AT, 201473_AT, 242794_AT,BP_ALL 211352_S_AT, 21294

_AT, 201471_S_AT, 235739_AT, 20

960_S_AT, 213763_AT, 205067_AT, 236561_AT, 220066_AT, 200

7

_AT, 205

91_AT, 20

665_AT, 20375

_AT, 225116_AT, 206157_AT, 201466_S_AT, 1552914_A_AT, 207700_S_AT,225115_AT, 1555832_S_AT, 222146_S_AT, 212124_AT, 225368_AT, 205312_AT,20

961_S_AT, 224859_AT, 216248_S_AT, 212171_X_AT, 39402_AT, 204622_X_AT,205463_S_AT, 235457_AT, 2123

7_AT, 229

30_AT, 21

559_S_AT, 222670_S_AT, 210512_S_AT, 211527_X_AT, 244414_AT, 242405_AT,220266_S_AT, 2132

1_AT, 224606_AT, 209189_AT, 210513_S_AT, 203935_AT, 212386_AT,225097_AT, 225557_AT, 223394_AT GOTERM_(—) 1554992_AT, 203665_AT, 205

91_AT, 39402_AT, 21

34_S_AT, 238669_AT, 15565

3_A_AT, BP_ALL 240

65_AT, 206171_AT, 219257_S_AT, 205067_AT, 202071_AT, 200

78_AT, 201170_S_AT, 2156

8_AT, 1562467_AT GOTERM_(—) 203

65_AT, 205891_AT, 203140_AT, 222062_AT, 39402_AT, 217757_AT, 205067_AT,220066_AT, BP_ALL 226218_AT, 204923_AT GOTERM_(—) 202540_S_AT,213891_S_AT, 201464_X_AT, 201465_S_AT, 212171_X_AT, 216248_S_AT,209659_AT, MF_ALL 205463_S_AT, 204622_X_AT, 241722_X_AT, 20

923_S_AT, 201473_AT, 2123

7_AT, 229

30_AT, 227107_AT, 235739_AT, 210512_S_AT, 236561_AT, 211527_X_AT,200878_AT, 20

751_X_AT, 1562467_AT, 20499

_S_AT, 202768_AT, 2132

1_AT, 221840_AT, 210513_S_AT, 1552553_A_AT, 20918

_AT, 221012_S_AT, 203753_AT, 203922_S_AT, 204

53_AT, 204715_AT, 201466_S_AT, 2

5295_AT, 203104_AT, 203935_AT, 201313_AT, 201995_AT, 2123

6_AT, 222146_S_AT, 203752_S_AT, 202539_S_AT GOTERM_(—) 212171_X_AT,212298_AT, 63825_AT, 205463_S_AT, 229

30_AT, 205566_AT, 203940_S_AT, BP_ALL 2

1

_X_AT, 236561_AT, 210512_S_AT,

7100_AT, 231527_X_AT, 210839_S_AT, 22

490_AT, 203665_AT, 203140_AT, 202241_AT, 210513_S_AT, 239519_AT,212190_AT, 221

15_AT, 225337_AT, 212343_S_AT, 219257_S_AT, 209392_AT, 210095_S_ATGOTERM_(—) 201464_X_AT, 201465_S_AT, 21902

_AT, 212171_X_AT, 2122

_AT, 205463_S_AT, 229

30_AT, BP_ALL 213763_AT, 2026

6_S_AT, 226389_S_AT, 236561_AT, 210512_S_AT, 211527_X_AT, 221

40_AT, 2132

1_AT, 2091

9_AT, 210513_S_AT, 239519_AT, 214054_AT, 203037_S_AT, 229116_AT,225738_AT, 2014

6_S_AT, 203935_AT, 203104_AT, 225115_AT, 225097_AT, 22536

_AT, 20

37_S_AT, 225557_AT, 210173_AT GOTERM_(—) 229221_AT, 214297_AT,212171_X_AT, 209555_S_AT, 205463_S_AT, 212014_X_AT, 211924_S_AT, CC_ALL214

66_AT, 226218_AT, 210916_S_AT, 229830_AT, 209994_S_AT, 206488_S_AT,1557905_S_AT, 23

542_AT, 210512_S_AT, 220066_AT, 211527_X_AT, 202071_AT, 2044

9_S_AT, 204736_S_AT, 204490_S_AT, 220307_AT, 210513_S_AT, 209

35_X_AT, 1552914_A_AT, 204105_S_AT, 202756_S_AT, 22

766_AT, 241929_AT, 210

45_S_AT, 224859_AT, 209993_AT GOTERM_(—) 214211_AT, 201464_X_AT,223723_AT, 201465_S_AT, 37152_AT, 210136_AT, 39402_AT, BP_ALL241722_X_AT, 1405_I_AT, 241938_AT, 204661_AT, 34210_AT, 205099_S_AT,200748_S_AT, 20

01_AT, 205067_AT, 201925_S_AT, 1562

67_AT, 209906_AT, 216017_S_AT, 213281_AT, 204655_AT, 201466_S_AT,239451_AT, 15565

3_A_AT, 212803_AT, 1555759_A_AT, 241773_AT, 201005_AT, 205098_ATGOTERM_(—) 202540_S_AT, 37152_AT, 21902

_AT, 2279

_AT, 216834_AT, 20247

_AT, 211352_S_AT, BP_ALL 201471_S_AT, 213763_AT, 24

0_S_AT, 2263

9_S_AT, 205067_AT, 1566901_AT, 236561_AT, 220066_AT, 202

_AT, 205891_AT, 203

5_AT, 20

891_AT, 225116_AT, 212143_S_AT, 207700_S_AT, 225115_AT, 215602_AT, 22536

_AT, 202

_S_AT, 241773_AT, 243556_AT, 2100

5_S_AT, 20253

_S_AT, 212171_X_AT, 218501_AT, 39402_AT, 227240_AT, 22339

_AT, 239818_X_AT, 208893_S_AT, 219

45_AT, 219908_AT, 210512_S_AT, 2191

3_S_AT, 211527_X_AT, 1554992_AT, 203140_AT, 20

92_S_AT, 202241_AT, 210513_S_AT, 1565754_X_AT, 22573

_AT, 1565752_AT, 20

935_AT, 210258_AT, 227697_AT, 225097_AT, 217591_AT, 2156

_AT GOTERM_(—) 212298_AT, 212171_X_AT, 63825_AT, 209555_S_AT, 39402_AT,205463_S_AT, 228708_AT, BP_ALL 229830_AT, 227107_AT, 205566_AT,204401_AT, 2064

_S_AT, 239

1

_X_AT, 203940_S_AT, 205067_AT, 203548_S_AT, 210512_S_AT, 236561_AT,220066_AT,

7100_AT, 211527_X_AT, 210

39_S_AT, 228490_AT, 203665_AT, 205

91_AT, 203140_AT, 202241_AT, 239519_AT, 210513_S_AT, 212190_AT,204715_AT, 221

15_AT, 206157_AT, 212143_S_AT, 225337_AT, 235669_AT, 235295_AT,1556583_A_AT, 228766_AT, 219257_S_AT, 209392_AT, 241929_AT, 210095_S_ATGOTERM_(—) 203665_AT, 203140_AT, 203233_AT, 227062_AT, 217757_AT,220066_AT, 22621

_AT, 224

59_AT, BP_ALL 1552914_A_AT GOTERM_(—) 217173_S_AT, 37152_AT, 219155_AT,209555_S_AT, 23

649_AT, 202068_S_AT, 212062_AT, BP_ALL 204401_AT, 226350_AT, 206

_S_AT, 22

766_AT, 214255_AT, 226302_AT, 241929_AT, 202067_S_AT, 201012_AT,209122_AT GOTERM_(—) 227069_AT, 229221_AT, 37152_AT, 212298_AT,210136_AT, 212014_X_AT, 221731_X_AT, 222

77_AT, BP_ALL 241938_AT, 210916_S_AT, 235739_AT, 202

28_S_AT, 1566901_AT, 230360_AT, 236561_AT, 204141_AT, 204489_S_AT,216017_S_AT, 204490_S_AT, 204998_S_AT, 20

620_S_AT, 201149_S_AT, 239519_AT, 201147_S_AT, 209

35_X_AT, 232649_AT, 204653_AT, 212190_AT, 2204

4_AT, 201005_AT, 243556_AT, 2119

6_AT, 233220_AT, 160020_AT, 212172_X_AT, 21624

_S_AT, 204622_X_AT, 227240_AT, 202191_S_AT, 218559_S_AT, 1557905_S_AT,204684_AT, 210512_S_AT, 202

27_S_AT, 222670_S_AT, 211527_X_AT, 201150_S_AT, 204465_S_AT,201248_S_AT, 1554

2_AT, 220935_S_AT, 210512_S_AT, 2091

9_AT, 215646_S_AT, 204619_S_AT, 212372_AT, 204105_S_AT, 229797_AT, 212

03_AT, 217279_X_AT, 215

8_AT, 211571_S_AT GOTERM_(—) 2014

4_X_AT, 201465_S_AT, 37152_AT, 210136_AT, 2122

_AT, 2162

_S_AT, 39402_AT, BP_ALL 205463_S_AT, 204622_X_AT, 1405_I_AT, 241938_AT,229

30_AT, 205099_S_AT, 227107_AT, 235739_AT, 2026

_S_AT, 2046

4_AT, 219845_AT, 205067_AT, 2022

4_S_AT, 221463_AT, 1562467_AT, 21

017_S_AT, 203665_AT, 205

1_AT, 213281_AT, 204655_AT, 239519_AT, 2091

9_AT, 204715_AT, 201466_S_AT, 235295_AT, 15565

3_A_AT, 212

03_AT, 1555759_A_AT, 210173_AT, 201005_AT, 20509

_AT GOTERM_(—) 212171_X_AT, 212124_AT, 211962_S_AT, 210513_S_AT,210512_S_AT, 201473_AT, 210173_AT, BP_ALL 211527_X_AT, 24193

_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 37152_AT, 219028_AT,212171_X_AT, 212298_AT, 39402_AT, BP_ALL 205463_S_AT, 201566_X_AT,223501_AT, 229

30_AT, 204923_AT, 213763_AT, 1566

01_AT, 205067_AT, 236561_AT, 2022

4_S_AT, 210512_S_AT, 211527_X_AT, 203140_AT, 213281_AT, 239519_AT,201565_S_AT, 210513_S_AT, 225116_AT, 223502_S_AT, 201466_S_AT,1552914_A_AT, 204035_AT, 225115_AT, 225097_AT, 212124_AT, 219257_S_AT,225368_AT, 224859_AT, 223394_AT GOTERM_(—) 214211_AT, 201464_X_AT,201465_S_AT, 37152_AT, 39402_AT, 221842_S_AT, 20074

_S_AT, BP_ALL 203940_S_AT, 23981

_X_AT, 200921_S_AT, 1566901_AT, 205067_AT, 202284_S_AT, 202859_X_AT,200920_S_AT, 203729_AT, 203665_AT, 203140_AT, 220266_S_AT, 213281_AT,202241_AT, 201466_S_AT, 1552914_A_AT, 212143_S_AT, 204035_AT, 201005_AT,224859_AT, 210095_S_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 229221_AT,21902

_AT, 227948_AT, 212014_X_AT, 210916_S_AT, BP_ALL 201041_S_AT,201471_S_AT, 235739_AT, 213763_AT, 217997_AT, 205067_AT, 202284_S_AT,236561_AT, 220066_AT, 204489_S_AT, 203665_AT, 204490_S_AT, 20499

_S_AT, 201149_S_AT, 201147_S_AT, 209835_X_AT, 225116_AT, 223502_S_AT,201466_S_AT, 212143_S_AT, 204035_AT, 225115_AT, 215602_AT, 225368_AT,243556_AT, 210095_S_AT, 205681_AT, 201012_AT, 212171_X_AT, 216248_S_AT,39402_AT, 21

501_AT, 204622_X_AT, 243797_AT, 241722_X_AT, 227240_AT, 223501_AT, 2020

6_AT, 1557905_S_AT, 200921_S_AT, 210512_S_AT, 200920_S_AT, 211527_X_AT,201150_S_AT, 217996_AT, 201148_S_AT, 1554992_AT, 203140_AT, 213281_AT,210513_S_AT, 1552553_A_AT, 1565754_X_AT, 201044_X_AT, 225

42_AT, 1565752_AT, 203

35_AT, 239451_AT, 227697_AT, 225097_AT, 219257_S_AT, 2156

_AT GOTERM_(—) 205

91_AT, 203140_AT, 203233_AT, 39402_AT, 205067_AT, 2022

4_S_AT, 226218_AT, 223501_AT, BP_ALL 224

59_AT, 223502_S_AT, 1552914_A_AT, 20

923_AT GOTERM 203140_AT, 205891_AT, 203665_AT, 39402_AT, 22621

_AT, 223501_AT, 223502_S_AT, 20

923_AT, BP_ALL 1552914_A_AT, 203233_AT, 222062_AT, 205067_AT, 2022

4_S_AT, 224

59_AT GOTERM_(—) 216442_X_AT, 210495_X_AT, 212271_X_AT, 22794

_AT, 210513_S_AT, 211719_X_AT, 1565754_X_AT, BP_ALL 202191_S_AT,212372_AT, 1565752_AT, 215602_AT, 214255_AT, 210512_S_AT, 211527_X_AT,212464_S_AT GOTERM_(—) 213391_S_AT, 201454_X_AT, 201465_S_AT, 219028_AT,221

41_S_AT, 201473_AT, 242794_AT BP_ALL 211352_S_AT, 212948_AT,201471_S_AT, 235739_AT, 20

960_S_AT, 213763_AT, 205067_AT 1554453_AT, 236561_AT, 200

78_AT, 205891_AT, 203753_AT, 225116_AT, 206157_AT, 201466_S_AT207700_S_AT, 225115_AT, 1555832_S_AT, 222146_S_AT, 212124_AT, 225368_AT,205312_AT, 20

961_S_AT, 216248_S_AT, 212171_X_AT, 39402_AT, 205463_S_AT, 204622_X_AT,235457_AT, 2123

7_AT, 229

30_AT, 218559_S_AT, 222670_S_AT, 210512_S_AT, 211527_X_AT, 244414_AT,242405_AT, 220266_S_AT, 213281_AT, 224606_AT, 209189_AT, 210513_S_AT,203935_AT, 212386_AT, 225097_AT, 225557_AT, 223394_AT GOTERM_(—)201464_X_AT, 201455_S_AT, 229221_AT, 219028_AT, 227946_AT, 212014_X_AT,210916_S_AT, BP_ALL 201041_S_AT, 201471_S_AT, 235739_AT, 213763_AT,217997_AT, 205067_AT, 2022

4_S_AT, 23

561_AT, 220066_AT, 2044

9_S_AT, 203665_AT, 204490_S_AT, 20499

_S_AT, 201149_S_AT, 201147_S_AT, 209835_X_AT, 225116_AT, 223502_S_AT,201466_S_AT, 212143_S_AT, 204035_AT, 225115_AT, 215602_AT, 225368_AT,243556_AT, 210095_S_AT, 2056

1_AT, 201012_AT, 212171_X_AT, 21624

_S_AT, 39402_AT, 21

501_AT, 204622_X_AT, 243797_AT, 241722_X_AT, 227240_AT, 223501_AT, 202

6_AT, 1557905_S_AT, 200922_S_AT, 210512_S_AT, 200920_S_AT, 211527_X_AT,201150_S_AT, 217996_AT, 201148_S_AT, 1554992_AT, 203140_AT, 213281_AT,210513_S_AT, 1552553_A_AT, 1565754_X_AT, 201044_X_AT, 225842_AT,1565752_AT, 203935_AT, 239451_AT, 227697_AT, 225097_AT, 219257_S_AT,215688_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 229221_AT, 219028_AT,227948_AT, 212014_X_AT, 210916_S_AT, BP_ALL 201041_S_AT, 201471_S_AT,235739_AT, 213763_AT, 217997_AT, 205067_AT, 2022

4_S_AT, 236561_AT, 220066_AT, 2044

9_S_AT, 203665_AT, 204490_S_AT, 20499

_S_AT, 201149_S_AT, 201147_S_AT, 209835_X_AT, 225116_AT, 223502_S_AT,201466_S_AT, 212143_S_AT, 204035_AT, 225115_AT, 215602_AT, 225368_AT,243556_AT, 210095_S_AT, 205681_AT, 201012_AT, 212171_X_AT, 21624

_S_AT, 39402_AT, 21

501_AT, 204622_X_AT, 243797_AT, 241722_X_AT, 227240_AT, 223501_AT, 2020

6_AT, 1557905_S_AT, 200921_S_AT, 210512_S_AT, 200920_S_AT, 211527_X_AT,201150_S_AT, 217996_AT, 201248_S_AT, 1554992_AT, 203140_AT, 2132

1_AT, 210513_S_AT, 1552553_A_AT, 1565754_X_AT, 201044_X_AT, 225842_AT,1565752_AT, 203935_AT, 239451_AT, 227697_AT, 225097_AT, 219257_S_AT,2156

_AT GOTERM_(—) 205891_AT, 203140_AT, 217757_AT, 203508_AT, 204

55_AT, 1405_I_AT, 1555759_A_AT, 224859_AT, BP_ALL 203939_AT,1552914_A_AT GOTERM_(—) 204035_AT, 212171_X_AT, 210513_S_AT,210512_S_AT, 202859_X_AT, 211527_X_AT, 20

27_S_AT BP_ALL GOTERM_(—) 202540_S_AT, 37152_AT, 215028_AT, 2279

_AT, 216834_AT, 202478_AT, 211352_S_AT, BP_ALL 201471_S_AT, 213763_AT,224480_S_AT, 226389_S_AT, 205067_AT, 15

6901_AT, 236561_AT, 2200

6_AT, 201170_S_AT, 2023

_AT, 203

65_AT, 2058

1_AT, 20

91_AT, 225116_AT, 212143_S_AT, 207700_S_AT, 225115_AT, 213602_AT, 22536

_AT, 2029

_S_AT, 241773_AT, 243556_AT, 210095_S_AT, 202539_S_AT, 212171_X_AT,218501_AT, 39402_AT, 227240_AT, 2232

_AT, 239

15_X_AT, 20

93_S_AT, 219845_AT, 219908_AT, 210512_S_AT, 219183_S_AT, 211527_X_AT,1562467_AT, 1554992_AT, 203140_AT, 20

92_S_AT, 202241_AT, 210513_S_AT, 1565754_X_AT, 22573

_AT, 1565752_AT, 203935_AT, 210258_AT, 227697_AT, 225097_AT, 217591_AT,2156

_AT GOTERM_(—) 205891_AT, 203140_AT, 203233_AT, 39402_AT, 205067_AT,202284_S_AT, 226218_AT, 223501_AT, BP_ALL 224859_AT, 223502_S_AT,1552914_A_AT, 204923_AT GOTERM_(—) 213503_X_AT, 21902

_AT, 39402_AT, 205463_S_AT, 22794

_AT, 1405_I_AT, 210427_X_AT, BP_ALL 229830_AT, 213763_AT, 205067_AT,220066_AT, 20

436_S_AT, 203939_AT, 203140_AT, 205

91_AT, 217757_AT, 20

16_X_AT, 204655_AT, 201590_X_AT, 225116_AT, 1552914_A_AT, 225115_AT,225097_AT, 203508_AT, 225368_AT, 1555759_A_AT, 234

59_AT GOTERM_(—) 160020_AT, 216017_S_AT, 201069_AT, 21350

_X_AT, 210427_X_AT, 201590_X_AT, 22421

_S_AT, BP_ALL 204

3_AT, 212143_S_AT, 206

35_AT, 218502_S_AT, 201995_AT, 203752_S_AT, 202

28_S_AT, 212

03_AT, 236561_AT, 202827_S_AT, 223092_AT, 225557_AT, 217279_AT,222651_S_AT, 2100

5_S_AT, 1569149_AT, 203751_X_AT GOTERM_(—) 203

_AT, 214453_S_AT, 20

655_AT, 1405_I_AT, 1555759_A_AT, 20

436_S_AT, 211676_S_AT, BP_ALL 202086_AT, 229

37_X_AT, 208438_S_AT, 213293_S_AT GOTERM_(—) 201464_X_AT, 201465_S_AT,229221_AT, 37152_AT, 212171_X_AT, 224967_AT, 205463_S_AT, BP_ALL221841_S_AT, 212014_X_AT, 211924_S_AT, 214

66_AT, 201473_AT, 222877_AT, 210916_S_AT, 229

30_AT, 1557905_S_AT, 206

35_AT, 219

45_AT, 1566901_AT, 210512_S_AT, 211527_X_AT, 1562467_AT, 201150_S_AT,204465_S_AT, 201148_S_AT, 2044

9_S_AT, 204490_S_AT, 220266_S_AT, 2132

1_AT, 201149_S_AT, 210

13_S_AT, 201147_S_AT, 209

35_X_AT, 204653_AT, 201466_S_AT, 212372_AT, 203935_AT, 204881_S_AT,201995_AT, 21

45_S_AT, 201324_AT, 201012_AT GOTERM_(—) 214211_AT, 209906_AT,223723_AT, 203665_AT, 39402_AT, 1405_I_AT, 204655_AT, 34230_AT, BP_ALL204661_AT, 20

099_S_AT, 20074

_S_AT, 239451_AT, 15565

3_A_AT, 205067_AT, 1555759_A_AT, 241773_AT, 201925_S_AT, 20509

_AT GOTERM_(—) 216442_X_AT, 210

95_X_AT, 21229

_AT, 210136_AT, 212171_X_AT, 22794

_AT, 23

519_AT, BP_ALL 210513_S_AT, 211719_X_AT, 1565754_X_AT, 202191_S_AT,212372_AT, 1565752_AT, 204105_S_AT, 215602_AT, 214255_AT, 210512_S_AT,211527_X_AT, 22464_S_AT GOTERM_(—) 201464_X_AT, 201465_S_AT, 39402_AT,20546

_S_AT, 2112

1_AT, 1405_I_AT, 204655_AT, BP_ALL 2091

9_AT, 201473_AT, 229

30_AT, 201

66_S_AT, 20

4_S_AT, 201315_AT, 227697_AT, 155658

_A_AT, 205067_AT, 2022

4_S_AT, 1555759_A_AT, 20

2_AT, 207

19_S_AT, 209122_AT GOTERM_(—) 160020_AT, 229221_AT, 227

9_AT, 212171_X_AT, 21229

_AT, 205463_S_AT, 212014_X_AT, BP_ALL 210916_S_AT, 219

30_AT, 1557905_S_AT, 202

2

_S_AT, 1566

01_AT, 236561_AT, 210512_S_AT, 202

27_S_AT, 211527_X_AT, 200

7

_AT, 204

9_S_AT, 204490_S_AT, 210513_S_AT, 235519_AT, 20

35_X_AT, 204653_AT, 203935_AT, 217279_X_AT, 203529_AT GOTERM_(—)219028_AT, 212171_X_AT, 216248_S_AT, 39402_AT, 204622_X_AT, 241722_X_AT,223501_AT, BP_ALL 201471_S_AT, 235739_AT, 213763_AT, 205067_AT,236561_AT, 202284_S_AT, 210512_S_AT, 211527_X_AT, 203140_AT, 203665_AT,20499

_S_AT, 210513_S_AT, 225116_AT, 223502_S_AT, 204035_AT, 203935_AT,225115_AT, 239451_AT, 227697_AT, 225097_AT, 219257_S_AT, 22536

_AT, 201012_AT, 205681_AT GOTERM_(—) 212171_X_AT, 39402_AT, 216243_S_AT,1405_I_AT, 204655_AT, 210513_S_AT, 223501_AT, MF_ALL 223502_S_AT,204035_AT, 212657_S_AT, 205067_AT, 210512_S_AT, 1555759_A_AT,202859_X_AT, 221463_AT, 211527_X_AT, 209827_S_AT GOTERM_(—) 205463_S_AT,212124_AT, 219257_S_AT, 1566901_AT, 2022

4_S_AT, 229

30_AT BP_ALL GOTERM_(—) 20114

_S_AT, 216442_X_AT, 210495_X_AT, 21342

_S_AT, 212171_X_AT, 213503_X_AT, CC_ALL 20

16_X_AT, 201149_S_AT, 210513_S_AT, 210427_X_AT, 201147_S_AT,201590_X_AT, 211719_X_AT, 235944_AT, 210512_S_AT, 211527_X_AT,201150_S_AT, 212464_S_AT KEGG_(—) 237252_AT, 209906_AT, 203

87_S_AT, 217757_AT, 211924_S_AT, 217552_X_AT, 214866_AT, PATHWAY210845_S_AT, 201925_S_AT, 203

_AT GOTERM_(—) 20114

_S_AT, 21

442_X_AT, 210495_X_AT, 212171_X_AT, 213503_X_AT, 208816_X_AT, CC_ALL201149_S_AT, 210513_S_AT, 210427_X_AT, 201147_S_AT, 201590_X_AT,211719_X_AT, 235944_AT, 210512_S_AT, 211527_X_AT, 201150_S_AT,212464_S_AT GOTERM_(—) 219028_AT, 212171_X_AT, 216248_S_AT, 39402_AT,204622_X_AT, 241722_X_AT, 223501_AT, BP_ALL 201471_S_AT, 235739_AT,213763_AT, 205067_AT, 236561_AT, 2022

4_S_AT, 210512_S_AT, 211527_X_AT, 203140_AT, 203665_AT, 2049

_S_AT, 210513_S_AT, 225116_AT, 223502_S_AT, 204035_AT, 203935_AT,225115_AT, 239451_AT, 227697_AT, 225097_AT, 219257_S_AT, 225368_AT,201012_AT, 205681_AT GOTERM_(—) 21902

_AT, 212171_X_AT, 216248_S_AT_S_AT, 39402_AT, 204622_X_AT, 241722_X_AT,223501_AT, BP_ALL 201471_S_AT, 235739_AT, 213763_AT, 205067_AT,236561_AT, 202284_S_AT, 210512_S_AT, 211527_X_AT, 203140_AT, 203665_AT,204998_S_AT, 210513_S_AT, 225116_AT, 223502_S_AT, 204035_AT, 203935_AT,225115_AT, 239451_AT, 227697_AT, 225097_AT, 219257_S_AT, 225368_AT,201012_AT, 2056

1_AT GOTERM_(—) 203140_AT, 39402_AT, 205067_AT, 202284_S_AT, 223501_AT,224859_AT, 223502_S_AT, BP_ALL 155291_A_AT, 204923_AT GOTERM_(—)203140_AT, 39402_AT, 205067_AT, 2022

_S_AT, 223501_AT, 224

59_AT, 223502_S_AT, BP_ALL 1552914_A_AT, 204923_AT GOTERM_(—) 203140_AT,39402_AT, 205067_AT, 2022

4_S_AT, 223501_AT, 224

59_AT, 223502_S_AT, BP_ALL 1552914_A_AT, 204923_AT GOTERM_(—)216442_X_AT, 210495_X_AT, 212171_X_AT, 39402_AT, 209555_S_AT, 217757_AT,205463_S_AT, CC_ALL 228708_AT, 210513_S_AT, 209549_AT, 211719_X_AT, 229

30_AT, 2064

8_S_AT, 2046

4_AT, 22

766_AT, 205067_AT, 210512_S_AT, 241

29_AT, 202005_AT, 211527_X_AT, 212464_S_AT GOTERM_(—) 201464_X_AT, 213

91_S_AT, 201465_S_AT, 219028_AT, 221

41_S_AT, 201473_AT, 242794_AT, BP_ALL 211352_S_AT, 21294

_AT, 201471_S_AT, 235739_AT, 20

960_S_AT, 213763_AT, 236561_AT, 200

7

_AT, 201753_AT, 225116_AT, 201466_S_AT, 223502_S_AT, 207700_S_AT,225115_AT, 1555

32_S_AT, 222146_S_AT, 212124_AT, 22536

_AT, 205312_AT, 20

961_S_AT, 212171_X_AT, 21

2

_S_AT, 204622_X_AT_, 235457_AT, 22

64_AT, 22350

_AT, 2123

7_AT, 21

559_S_AT, 210512_S_AT, 212670_S_AT, 211527_X_AT, 24

14_AT, 220266_S_AT, 242405_AT, 2132

1_AT, 224606_AT, 210513_S_AT, 2091

9_AT, 203935_AT, 2123

6_AT, 225097_AT, 225557_AT, 2233

4_AT GOTERM_(—) 213

91_S_AT, 201464_X_AT, 201465_S_AT, 215028_AT, 221

41_S_AT, 201473_AT, 242794_AT, BP_ALL 211352_S_AT, 21294

_AT, 201471_S_AT, 235739_AT, 20

960_S_AT, 213763_AT, 2050

7_AT, 236561_AT, 200

78_AT, 203665_AT, 203753_AT, 225116_AT, 201466_S_AT, 1552914_A_AT,207700_S_AT, 225115_AT, 1555

32_S_AT, 222146_S_AT, 212124_AT, 2253

_AT, 205312_AT, 20

961_S_AT, 224

59_AT, 21624

_S_AT, 212171_X_AT, 39402_AT, 205463_S_AT, 204622_X_AT, 235457_AT,212387_AT, 229

30_AT, 218559_S_AT, 222670_S_AT, 210512_S_AT, 211527_X_AT, 244414_AT,242405_AT, 220266_S_AT, 2132

1_AT, 224606_AT, 2091

9_AT, 210513_S_AT, 203935_AT, 2123

6_AT, 225097_AT, 225557_AT, 223394_AT GOTERM_(—) 203665_AT, 203140_AT,205891_AT, 213503_X_AT, 212171_X_AT, 205463_S_AT, 20

16_X_AT, BP_ALL 210427_X_AT, 210513_S_AT, 201590_X_AT, 229

30_AT, 206

35_AT, 210512_S_AT, 220066_AT, 211527_X_AT GOTERM_(—) 209906_AT,39402_AT, 15565

3_A_AT, 205067_AT, 241773_AT, 201925_S_AT, 204661_AT, 34230_AT, BP_ALL205099_S_AT, 20609

_AT GOTERM_(—) 160020_AT, 201069_AT, 216017_S_AT, 212143_S_AT, 206

35_AT, 201995_AT, 203752_S_AT, BP_ALL 202

2

_S_AT, 212803_AT, 202

27_S_AT, 217279_X_AT, 210095_S_AT, 203751_X_AT, 1569149_AT

indicates data missing or illegible when filed

The gene expression patterns induced by Copaxone® and Polimunoltreatment were compared directly. The differential expression resultswere filtered based on the variability in observed control treatmenteffects relative to previous studies, to obtain a conservative subset ofhighest-confidence probesets. These analyses found that 27highest-confidence probesets, representing 21 distinct genes, differedsignificantly by adjusted p value in expression between the twotreatments (14 probesets downregulated, 13 upregulated by Polimunolrelative to Copaxone). The upregulated and downregulated probesets areillustrated in Table 13 and Table 14, respectively.

TABLE 13 Human monocyte study: probesets upregulated by Polimunolrelative to Copaxone ® ID Gene raw.FC AveExpr P.Value adj.P.Val202436_s_at CYP1B1 1.328778115 10.99251935 2.76E−15 1.51E−10 202435_s_atCYP1B1 1.291947504 11.10690276 1.98E−11 2.70E−07 202434_s_at CYP1B11.34300307 8.896124188 5.54E−10 3.79E−06 229055_at GPR68 1.2333033067.906128859 3.58E−09 1.50E−05 202437_s_at CYP1B1 1.283470087 11.355027595.53E−09 1.96E−05 212665_at TIPARP 1.170151206 9.316307674 2.29E−070.000543566 1554966_a_at DOC1 1.127401263 8.443050186 5.83E−070.001274168 204684_at NPTX1 1.121904593 10.50026157 4.27E−06 0.00556324229354_at PDCD6 1.082379299 10.56416164 8.47E−06 0.009858651 /// AHRR206710_s_at EPB41L3 1.17828072 6.683285506 3.11E−05 0.021766496204135_at DOC1 1.093724798 8.540804821 4.46E−05 0.028883673 1569690_atCCDC36 1.140648392 5.595578016 5.04E−05 0.030714439 211067_s_at GAS71.080052886 9.66677524 5.29E−05 0.031621345

TABLE 14 Human monocyte study: probesets downregulated by Polimunolrelative to Copaxone ® ID Gene raw.FC AveExpr P.Value adj.P.Val230927_at — −1.171546521 6.290190151 2.87E−06 0.004124895 206170_atADRB2 −1.142744253 8.033661912 7.30E−06 0.008675631 228826_at RNF43−1.090334004 8.930697832 9.19E−06 0.010052917 1554676_at PRG1−1.337462167 7.452885159 1.08E−05 0.010571079 1557359_at LOC285758−1.113608349 9.441580738 1.43E−05 0.012763184 229934_at — −1.1460007639.629181433 1.67E−05 0.013799705 244190_at THAP5 −1.235324953 3.964047551.70E−05 0.013885917 1556346_at COTL1 −1.23259647 9.131189047 1.97E−050.01563098 215111_s_at TSC22D1 −1.115773148 9.642583368 2.19E−050.016510136 235274_at — −1.142519223 7.012670757 2.86E−05 0.0203443591558782_a_at LOC644137 −1.13456131 8.05846686 3.69E−05 0.024635148201147_s_at TIMP3 −1.069861862 11.50473352 5.32E−05 0.031621345224559_at MALAT1 −1.221208621 9.943150851 7.51E−05 0.039950998210592_s_at SAT1 −1.20105501 9.927587911 8.05E−05 0.042336898

The gene with the highest fold change among those upregulated byPolimunol relative to Copaxone® was CYP1B1 (adj p<1.5e-10), a member ofthe cytochrome P450 superfamily of enzymes. All four present probesetsfor this gene in this study showed similar results, as exemplified inTable 13. As shown in FIG. 25a , CYP1B1 is significantly upregulated byPolimunol stimulation in human THP-1 monocyte cell line compared toCopaxone® stimulation at 6 hours. A second example is shown in Table 13and FIG. 25b , a probeset for GPR68 which was also upregulated byPolimunol relative to Copaxone® (adj p<1.5e-5). Two probesets for theDOC1 gene were significantly upregulated by Polimunol relative toCopaxone, as shown in Table 13.

One of the probesets downregulated by Polimunol relative to Copaxone®was ADRB2, the gene encoding the beta-2 adrenergic receptor. As shown inFIG. 26, ADRB2 is significantly downregulated by Polimunol stimulationin human THP-1 monocyte cell line compared to Copaxone® stimulation at 6hours.

Discussion Example 9

Copaxone® treatment was compared with treatment with the purportedgeneric Polimunol (manufactured by Synthon), as well as a mannitolcontrol. More than 80% of the pathways that enriched among topupregulated genes in the previous study were also enriched among topupregulated genes in the current study. The results show concordancewith the earlier study and confirm the gene expression patternsassociated with Copaxone treatment of human monocytes—i.e. the complex,yet consistent mode of action of Copaxone® in this immunological celltype.

As an example at the individual gene level, IL1RN was significantlyupregulated (adjusted p 2.8e-10), consistent with the previous studydescribed in Example 1. This gene encodes for the protein IL-1ra, whichinhibits the activities of pro-inflammatory cytokines IL-1a and IL-1b.

Overall, the results demonstrated that the effects of the complexbiological mechanism of Copaxone® observed in prior studies weremechanistically consistent with the effects observed in this study,corroborating the validity of this approach for studying glatiramoidfunctionality in treatment paradigms.

The study also identified significant differences between Copaxone® andSynthon's Polimunol. The results show that 27 highest-confidenceprobesets, representing 21 distinct genes, differed significantly byadjusted p value in expression between the two treatments (14 probesetsdownregulated, 13 upregulated by Polimunol relative to Copaxone).

The gene with the highest fold change among those upregulated byPolimunol relative to Copaxone® was CYP1B1 (adj p<1.5e-10), a member ofthe cytochrome P450 superfamily of enzymes. The cytochrome P450 proteinsare monooxygenases which catalyze many reactions involved in drugmetabolism.

A second example is a probeset for GPR68 which was also upregulated byPolimunol relative to Copaxone® (adj p<1.5e-5). After traumatic braininjury, cerebral cortical astrocytes abundantly expressed GPR68,suggesting a role in reactive astrogliosis.

Two probesets for the DOC1 gene were significantly upregulated byPolimunol relative to Copaxone®. DOC1 is also known as CDK2AP1, orcyclin-dependent kinase 2 associated protein 1. DOC1 has been implicatedas a locus for susceptibility to MS. (International Multiple SclerosisGenetics Consortium (IMSGC), Genes Immun., 2010). One of the probesetsdownregulated by Polimunol relative to Copaxone was ADRB2, the geneencoding the beta-2 adrenergic receptor. Agonists for this receptor havebeen reported to affect antigen cross-presentation by dendritic cells(Hervé et al, J Immunol, 2013), alter cytokine secretion in human PBMC(Hilbert et al, Plos One, 2013), and change the proportions of myeloidcells in mouse brain under TNFα treatment (Laureys et al, JNeuroinflammation, 2014). In addition, signaling via this receptor inFOXP3+ regulatory T cells has been shown to enhance the suppressivefunction of these cells (Guereschi et al, Eur J Immunol, 2013). Thisfunctionality coupled with the observed expression levels of ADRB2 inFIG. 26 warrants further investigation.

These initial studies show clear and significant differences betweenPolimunol and Copaxone® in terms of impact on genomic profiling,including expression of genes with relevance for safety. Follow-onexperiments are currently underway in both THP-1 cells and other modelsystems to further elucidate the differences identified to date.Substantial differences between Polimunol and Copaxone® were alsoidentified using physicochemical methods and biological methods.Therefore, the gene expression differences described here, albeit subtlein terms of fold change, may represent chronic treatment effects thatcould have a clinically significant impact, and warrant furtherinvestigation in the interest of keeping MS patients safe.

Example 10 Differences in Gene Expression Induced by Polimunol VersusBranded GA in Mouse Splenocyte Gene Expression Studies

Immunological cells, particularly T cells, are critical to the antigenicmechanism of action of Copaxone®, thus post-treatment gene expressionmodulation needs to examine such relevant cell types, includinglymphocytes.

As one approach to modeling these effects, a splenocyte system wasutilized, in which mice were first immunized with either Copaxone® orPolimunol, and then sacrificed, having the splenocytes stimulatedex-vivo with Copaxone®, Polimunol, or medium. This model was used tosimulate switching between medications compared with consistent use ofone medicine or the other. A total of 157 samples were tested, and geneexpression was measured using the Mouse Genome 430 2.0 Affymetrix chip.

Some similarities are observed between the genes modulated by Copaxone®in a mouse splenocyte model and in a human monocyte (THP-1) model: aprior study indicated that 1,378 genes were modulated by

Copaxone in both systems, while another 6,691 were modulated only insplenocytes and another 2,121 were modulated only in THP-1 cells(MSBoston Joint ACTRIMS-ECTRIMS 2014 Meeting, P282). These findingsindicate that the majority of the impact of glatiramoids is cell typeand tissue specific, including different interactions with lymphocytesversus antigen presenting cells, and thus several differentimmunologically relevant model systems are required to study the variousimplications of treatment with this NBCD.

Copaxone®-Modulated Genes Mechanism of Action (MoA)

Analyzing splenocytes from mice immunized by Copaxone® and lateractivated with Copaxone®, 16,647 probesets were significantly modulatedrelative to medium (8,342 upregulated and 8,305 downregulated). The factthat over one third of the total probesets expressed in this tissue(i.e. 22,524 probesets called present on the chip) are significantlydownregulated, and similarly over one third significantly upregulated,by Copaxone® treatment demonstrates the complexity of Copaxone'smechanism of action in this model system.

Copaxone® treatment upregulated key anti-inflammatory cytokines I110 and114 (adj p<2.3e-24 and 5.1e-35, respectively; FIG. 27a-b ) as well asmarkers of regulatory T cells, Foxp3 and Gpr83 (adj p<3.4e-23 for Foxp3;adj p<4.2e-33 and 9.0e-31 for the two Gpr83 probesets; FIG. 27c-d ).Copaxone® downregulated pro-inflammatory cytokines, such as 1112a(adjusted p<8.3e-31; FIG. 27e ). Consistently similar effects wereobserved for both immunization conditions (p values given abovecorrespond to Copaxone® immunization, and are within the same order ofmagnitude for immunization by Polimunol).

Copaxone®-Modulated Pathways

After imposing a conservative fold change filter of |FC|≧2, 411probesets are upregulated by Copaxone® relative to medium (inCopaxone-immunized mice), and these probesets enrich for 76 pathways.These pathways include relevant aspects of Copaxone®'s mechanism ofaction such as the cytokine-cytokine receptor interaction pathwayidentified previously in the THP-1 study for Copaxone mechanism ofaction (as well as differences observed with Polimunol). Similarly, 485downregulated probesets are detected, which enrich for 56 pathways. Boththe upregulated and downregulated pathways are depicted in FIG. 28. Thefull list of pathways entiched among top probesets modulated byCopaxone® relative to medium is provided in Table 15.

TABLE 15 Pathways enriched among top probesets modulated by Copaxone ®relative to medium in splenocytes from mice immunized with Copaxone ®(Pathways enriched among top upregulated probesets listed first followedby pathways enriched among top downregulated probesets). Categery TermCount Pvalue Fold Enrichment Benjamini GOTERM_MF_ALL GO:0005125-cytokine activity 20 4.24E−14 9.93177388 2.11E−11 KEGG_PATHWAYmmu04060: Cytokine-cytokine receptor interaction 29 1.86E−13 5.155443712.36E−11 GOTERM_CC_ALL GO: 0005576-extracellular region 44 2.62E−133.56241762 5.65E−11 GOTERM_CC_ALL GO: 0005615-extracellular space 262.29E−12 5.71896261 2.47E−10 GOTERM_CC_ALL GO: 0044421-extracellularregion part 29 5.96E−12 4.84008694 4.29E−10 GOTERM_BP_ALL GO:0006955-immune response 34 1.04E−11 3.99299275 1.66E−08 KEGG_PATHWAYmmu04630: lak-STAT signaling pathway 22 2.63E−10 5.24077519 1.67E−08GOTERM_BP_ALL GO: 0002376-immune system process 42 2.48E−09 2.765065711.98E−06 GOTERM_BP_ALL GO: 0016126-sterol biosynthetic process 106.57E−09 15.1694577 3.49E−06 GOTERM_CC_ALL GO: 0009897-external side ofplasma membrane 17 3.35E−07 4.86392974 1.81E−05 GOTERM_BP_ALL GO:0008299-isoprenoid biosynthetic process 8 5.51E−08 19.4169059 2.20E−05GOTERM_BP_ALL GO: 0016125-sterol metabolic process 12 8.93E−088.56628202 2.85E−05 GOTERM_CC_ALL GO: 0009986-cell surface 19 9.95E−074.01671583 4.30E−05 GOTERM_BP_ALL GO: 0006694-steroid biosyntheticprocess 11 1.64E−07 9.31334149 4.35E−05 GOTERM_BP_ALL GO:0006695-cholesterol biosynthetic process 8 3.93E−07 15.3291362 7.83E−05GOTERM_BP_ALL GO: 0050896-response to stimulus 65 3.63E−07 1.847334438.26E−05 KEGG_PATHWAY mmu00900: Terpenoid backbone biosynthesis 76.27E−06 12.8270722 0.00026558 KEGG_PATHWAY mmu00100: Steroidbiosynthesis 7 1.06E−05 11.9108527 0.00033672 GOTERM_BP_ALL GO:0008202-steroid metabolic process 13 2.89E−06 5.56808331 0.00035349GOTERM_BP_ALL GO: 0008203-cholesterol metabolic process 10 2.70E−068.09037746 0.00035891 GOTERM_BP_ALL GO: 0008284-positive regulation ofcell proliferation 18 2.13E−06 3.99585716 0.00037779 GOTERM_BP_ALL GO:0006720-isoprenoid metabolic process 8 2.40E−06 12.1355662 0.00038277GOTERM_BP_ALL GO: 0033138-positive regulation of peptidyl-serinephospherylation 5 2.66E−06 36.4066986 0.00038457 GOTERM_BP_ALL GO:0050730-regulation of peptidyl-tyrosine phosphorylation 9 3.40E−069.36172249 0.00038657 GOTERM_MF_ALL GO: 0005102-receptor binding 242.03E−06 3.13177103 0.00050318 GOTERM_BP_ALL GO: 0042325-regulation ofphosphorylation 19 6.54E−06 3.51130595 0.00069403 GOTERM_BP_ALL GO:0001932-regulation of protein amino acid phosphorylation 12 1.11E−055.39358497 0.00110231 GOTERM_BP_ALL GO: 0051174-regulation of phosphorusmetabolic process 19 1.22E−05 3.35789938 0.00114199 GOTERM_BP_ALL GO:0019220-regulation of phosphate metabolic process 19 1.22E−05 3.357899380.00114199 GOTERM_BP_ALL GO: 0008610-lipid biosynthetic process 182.07E−05 3.3779411 0.00173185 GOTERM_BP_ALL GO: 0050731-positiveregulation of peptidyl-tyresine phosphorylation 7 2.01E−05 11.58394950.00177599 GOTERM_BP_ALL GO: 0042127-regulation of cell proliferation 242.57E−05 2.68024775 0.00204526 GOTERM_BP_ALL GO: 0001934-positiveregulation of protein amino acid 8 2.96E−05 8.56628202 0.00208413phosphorylation GOTERM_BP_ALL GO: 0010740-positive regulation of proteinkinase cascade 10 2.75E−05 6.17062688 0.00208529 GOTERM_BP_ALL GO:0010627-regulation of protein kinase cascade 13 2.92E−05 4.464972470.00210456 GOTERM_BP_ALL GO: 0033135-regulation of peptidyl-serinephosphorylation 5 3.48E−05 22.7541866 0.00231024 GOTERM_BP_ALL GO:0042327-positive regulation of phosphorylation 8 4.38E−05 8.090377460.00279017 GOTERM_BP_ALL GO: 0045937-positive regulation of phosphatemetabolic process 8 5.28E−05 7.87171861 0.00323223 GOTERM_BP_ALL GO:0010562-positive regulation of phosphorus metabolic process 8 5.28E−057.87171861 0.00323223 GOTERM_BP_ALL GO: 0048522-positive regulation ofcellular process 41 0.00014045 1.83826926 0.00825294 GOTERM_BP_ALL GO:0006952-defense response 18 0.0001494 2.88687478 0.00846421GOTERM_BP_ALL GO: 0006629-lipid metabolic process 26 0.000198182.24306674 0.01046917 GOTERM_BP_ALL GO: 0006066-alcohol metabolicprocess 18 0.00019444 2.82465765 0.01062493 GOTERM_BP_ALL GO:0051251-positive regulation of lymphocyte activation 10 0.000372814.43984129 0.01839122 GOTERM_BP_ALL GO: 0031399-regulation of proteinmodification process 12 0.00036131 3.70237613 0.01839468 GOTERM_BP_ALLGO: 0008219-cell death 24 0.00038581 2.24041222 0.01845504 GOTERM_BP_ALLGO: 0006915-apoptosis 23 0.00041493 2.28161871 0.01925699 GOTERM_BP_ALLGO: 0016265-death 24 0.00049622 2.20090873 0.02006939 GOTERM_BP_ALL GO:0002696-positive regulation of leukocyte activation 10 0.000446784.33413078 0.02013394 GOTERM_BP_ALL GO: 0012501-programmed cell death 230.00046402 2.2631191 0.02032837 GOTERM_BP_ALL GO: 0002694-regulation ofleukocyte activation 12 0.0005166 3.55187303 0.0203686 GOTERM_BP_ALL GO:0050867-positive regulation of cell activation 10 0.00053242 4.233337040.02047943 GOTERM_BP_ALL GO: 0043410-positive regulation of MAPKKKcascade 6 0.00049453 8.73760766 0.02052261 GOTERM_BP_ALL GO:0009967-positive regulation of signal transduction 11 0.000482963.88809402 0.02058357 GOTERM_BP_ALL GO: 0050865-regulation of cellactivation 12 0.00059269 3.49504306 0.02223545 GOTERM_BP_ALL GO:0031401-positive regulation of protein modification process 8 0.00068675.29551979 0.02512736 GOTERM_BP_ALL GO: 0010647-positive regulation ofcell communication 11 0.0007042 3.70808967 0.02518163 GOTERM_BP_ALL GO:0051048-negative regulation of secretion 5 0.00076246 11.37709330.02664025 GOTERM_BP_ALL GO: 0048568-embryonic organ development 100.00080674 4.00073611 0.02756213 GOTERM_BP_ALL GO: 0010604-positiveregulation of macromolecule metabolic process 23 0.00085004 2.16370560.02841182 GOTERM_BP_ALL GO: 0048518-positive regulation of biologicalprocess 42 0.0009007 1.66566595 0.0288702 GOTERM_MF_ALL GO:0016705-oxidoreductase activity, acting on paired donors, 9 0.000295435.1901528 0.02894292 with incorporation GOTERM_BP_ALL GO:0044255-cellular lipid metabolic process 20 0.00088925 2.326306620.02909335 GOTERM_MF_ALL GO: 0042379-chemokine receptor binding 60.00035759 9.32723112 0.02919116 GOTERM_MF_ALL GO: 0004888-transmembranereceptor activity 18 0.00042544 2.64847303 0.02976082 GOTERM_MF_ALL GO:0019955-cytokine binding 9 0.00018429 5.54809437 0.0300713 GOTERM_BP_ALLGO: 0046888-negative regulation of hormone secretion 4 0.001018718.2033493 0.03195084 GOTERM_MF_ALL GO: 0008009-chemokine activity 60.00028629 9.75119617 0.03495115 GOTERM_BP_ALL GO: 0042180-cellularketone metabolic process 20 0.00120964 2.26833013 0.0364004GOTERM_BP_ALL GO: 0016053-organic acid biosynthetic process 100.00118661 3.79236443 0.03640669 GOTERM_BP_ALL GO: 0046394-carboxylicacid biosynthetic process 10 0.00118661 3.79236443 0.03640669GOTERM_BP_ALL GO: 0051249-regulation of lymphocyte activation 110.00131104 3.422852 0.0386639 KEGG_PATHWAY mmu05320: Autoimmune thyroiddisease 7 0.00172331 5.21099806 0.04286406 GOTERM_BP_ALL GO:0009611-response to wounding 14 0.00154486 2.77007489 0.04458422GOTERM_BP_ALL GO: 0006954-inflammatory response 11 0.00158927 3.33728070.04502272 GOTERM_BP_ALL GO: 0050864-regulation of B cell activation 70.00163582 5.42227425 0.04550354 GOTERM_CC_ALL GO: 0044425-membrane part167 3.13E−15 1.63662801 7.90E−13 GOTERM_CC_ALL GO: 0031224-intrinsic tomembrane 140 8.73E−15 1.77744709 1.11E−12 GOTERM_CC_ALL GO:0016021-integral to membrane 135 3.09E−14 1.78531887 2.61E−12GOTERM_MF_ALL GO: 0004872-receptor activity 59 6.67E−15 3.078392223.10E−12 GOTERM_CC_ALL GO: 0016020-membrane 172 3.65E−12 1.504867012.32E−10 GOTERM_MF_ALL GO: 0004871-signal transducer activity 631.62E−12 2.59629647 3.77E−10 GOTERM_MF_ALL GO: 0060089-moleculartransducer activity 63 1.62E−12 2.59629647 3.77E−10 GOTERM_BP_ALL GO:0006955-immune response 40 6.54E−13 3.77617866 1.06E−09 GOTERM_MF_ALLGO: 0004888-transmembrane receptor activity 33 3.17E−11 3.967963184.91E−09 GOTERM_BP_ALL GO: 0002376-immune system process 53 7.56E−122.80481986 6.14E−09 GOTERM_CC_ALL GO: 0009986-cell surface 27 2.11E−104.47916667 1.07E−08 GOTERM_CC_ALL GO: 0005886-plasma membrane 831.60E−09 1.91980807 6.79E−08 GOTERM_CC_ALL GO: 0005576-extracellularregion 42 1.08E−08 2.66843972 3.93E−07 GOTERM_MF_ALL GO:0030246-carbohydrate binding 21 1.71E−08 4.64841968 1.99E−06GOTERM_CC_ALL GO: 0044421-extracellular region part 26 1.42E−073.40521443 4.51E−06 KEGG_PATHWAY mmu04640: Hematopoietic cell lineage 142.50E−07 5.97693804 2.75E−05 GOTERM_BP_ALL GO: 0009605-response toexternal stimulus 33 7.98E−08 2.90017325 4.32E−05 GOTERM_CC_ALL GO:0009897-external side of plasma membrane 18 1.84E−06 4.04135338 5.20E−05GOTERM_BP_ALL GO: 0050896-response to stimulus 77 2.55E−07 1.759121488.30E−05 GOTERM_BP_ALL GO: 0007166-cell surface receptor linked signaltransduction 43 2.53E−07 2.3390549 0.00010269 GOTERM_BP_ALL GO:0009611-response to wounding 22 9.96E−07 3.49912207 0.00026984GOTERM_BP_ALL GO: 0002682-regulation of immune system process 251.60E−06 3.07409502 0.00037039 GOTERM_CC_ALL GO: 0005615-extracellularspace 19 1.75E−05 3.279544 0.00044365 GOTERM_BP_ALL GO: 0002684-positiveregulation of immune system process 19 4.74E−06 3.58736973 0.00096165GOTERM_BP_ALL GO: 0048584-positive regulation of response to stimulus 175.63E−06 3.91741369 0.0010166 GOTERM_BP_ALL GO: 0006952-defense response23 8.45E−06 2.96521518 0.00137227 GOTERM_MF_ALL GO: 0005529-sugarbinding 13 1.92E−05 4.6322231 0.00178054 GOTERM_BP_ALL GO:0050778-positive regulation of immune response 14 1.56E−05 4.35867430.00230833 GOTERM_CC_ALL GO: 0044459-plasma membrane part 46 0.000116251.79088802 0.00268093 GOTERM_BP_ALL GO: 0050776-regulation of immuneresponse 16 5.03E−05 3.46849003 0.00679349 GOTERM_MF_ALL GO:0005539-glycosaminoglycan binding 8 0.00012123 6.87497365 0.00935188GOTERM_BP_ALL GO: 0007155-cell adhesion 20 0.00010998 2.747923440.0136546 GOTERM_BP_ALL GO: 0022610-biological adhesion 20 0.000109982.74792344 0.0136546 GOTERM_BP_ALL GO: 0007626-locomotory behavior 140.0001342 3.56274248 0.01545668 GOTERM_MF_ALL GO: 0008201-heparinbinding 7 0.00024088 7.57520244 0.01587561 GOTERM_MF_ALL GO:0001871-pattern binding 8 0.00029954 5.99356677 0.01726258 GOTERM_MF_ALLGO: 0030247-polysaccharide binding 8 0.00029954 5.99356677 0.01726258GOTERM_BP_ALL GO: 0006909-phagocytosis 8 0.00017473 6.5034188 0.01759075GOTERM_BP_ALL GO: 0032501-multicellular organismal process 77 0.000170321.47960251 0.01828376 GOTERM_BP_ALL GO: 0006954-inflammatory response 140.00020677 3.41429487 0.01957233 GOTERM_BP_ALL GO: 0042330-taxis 100.00022296 4.72022333 0.01992884 GOTERM_BP_ALL GO: 0006935-chemotaxis 100.00022296 4.72022333 0.01992884 GOTERM_CC_ALL GO: 0005578-proteinaceousextracellular matrix 9 0.00121761 4.19921875 0.0254587 GOTERM_BP_ALL GO:0007186-G-protein coupled receptor protein signaling pathway 170.00035255 2.79500864 0.02970748 GOTERM_MF_ALL GO:0001664-G-protein-coupled receptor binding 7 0.00063894 6.391577060.03248313 GOTERM_MF_ALL GO: 0008009-chemokine activity 6 0.000726787.96871945 0.03324267 GOTERM_BP_ALL GO: 0008037-cell recognition 60.00044777 8.77961539 0.03406274 GOTERM_BP_ALL GO: 0050900-leukocytemigration 7 0.00043774 6.82858974 0.03494842 GOTERM_MF_ALL GO:0042379-chemokine receptor binding 6 0.00090307 7.62225339 0.03747238GOTERM_MF_ALL GO: 0004930-G-protein coupled receptor activity 120.0010892 3.24651533 0.03823098 GOTERM_BP_ALL GO: 0048583-regulation ofresponse to stimulus 19 0.00053982 2.50469508 0.03909905 GOTERM_BP_ALLGO: 0060326-cell chemotaxis 6 0.00057152 8.36153846 0.03958565GOTERM_BP_ALL GO: 0030595-leukocyte chemotaxis 6 0.00057152 8.361538460.03958565 GOTERM_MF_ALL GO: 0005102-receptor binding 21 0.001053372.23938466 0.04001704 GOTERM_CC_ALL GO: 0031012-extracellular matrix 90.00218595 3.83928571 0.04185565 GOTERM_BP_ALL GO: 0007165-signaltransduction 51 0.00074467 1.58780278 0.04918842

Copaxone® MoA Discussion

More than two thirds of the probesets expressed in the spleen weresignificantly modulated by Copaxone® treatment, and the top modulatedprobesets in either direction were enriched for many relevant pathways,including immune response and cytokine-cytokine receptor interactionpathways. Key anti-inflammatory cytokines, such as 1110 and 114, andregulatory T cell markers, such as Foxp3 and Gpr83, are upregulated byCopaxone®, while pro-inflammatory cytokines, such as 1112a, isdownregulated by Copaxone® treatment in this model system, consistentwith induction of a Th1 to Th2 shift. Thus, these studies help toillustrate the complexity of Copaxone's mechanism of action (impactingthousands of genes in over 100 different pathways), and providevalidation of the experimental system

Polimunol and Copaxone Comparison: Differentially Expressed Genes, UnderCopaxone Immunization

When splenocytes from Copaxone-immunized mice were activated withPolimunol and compared to activation by Copaxone® (as reported in theprior section), controlling for mannitol control, 223 probesets werefound to be differentially expressed (208 were upregulated, 15 weredownregulated). The top 25 upregulated probesets by Polimunol versusCopaxone are reported in Table 16, and include many interferon-inducedgenes as will be further discussed in the pathway enrichment sectionbelow. The 15 downregulated probesets by Polimunol versus Copaxone® arereported in Table 17.

Polimunol and Copaxone® Comparison: Differentially Expressed Genes,Under Polimunol Immunization

When splenocytes from Polimunol-immunized mice were activated withCopaxone® versus Polimunol, 431 probesets were found to bedifferentially expressed when both were corrected for medium (301 wereupregulated, 130 were downregulated). The top 25 upregulated probesetsby Polimunol versus Copaxone® are reported in Table 18 and consistentlywith the reciprocal study design (prior paragraph) include manyinterferon induced genes, and the top 25 downregulated probesets byPolimunol versus Copaxone® are reported in Table 19.

TABLE 16 Top 25 probesets upregulated by Polimunol versus Copaxone ® Insplenocytes from Copaxone ®-immunized mice Probeset Gene raw.FC P.Valueadj.P.Val. 1421551_s_at Ifi202b 1.48 6.69E−15 3.02E−10 1451905_a_at Mx11.75 2.21E−14 4.98E−10 1421998_at Tor3a 1.29 9.33E−14 1.40E−091457666_s_at Ifi202b /// 1.49 1.25E−13 1.41E−09 LOC100044068 1424339_atOasl1 1.46 2.05E−13 1.69E−09 1418293_at Ifit2 1.38 2.24E−13 1.69E−091423555_a_at Ifi44 1.62 2.85E−13 1.84E−09 1425917_at Ifi44l 1.634.06E−12 2.29E−08 1421596_s_at Ifi44l 1.63 1.40E−11 7.03E−08 1456164_atAW011738 1.20 2.32E−11 9.03E−08 1450454_at Tor3a 1.25 2.40E−11 9.03E−081449455_at Hck 1.16 4.06E−11 1.33E−07 1448775_at Gm16340 /// Ifi203 ///1.21 4.16E−11 1.33E−07 LOC100862473 1438868_at Phf11d 1.25 4.42E−111.33E−07 1428660_s_at Tor3a 1.25 5.25E−11 1.41E−07 1434401_at Zcchc21.16 5.31E−11 1.41E−07 1418191_at Usp18 1.39 1.10E−10 2.71E−071450027_at Sdc3 1.25 1.14E−10 2.71E−07 1435331_at Pyhin1 1.19 2.12E−104.79E−07 1436120_at Setdb2 1.16 2.43E−10 5.21E−07 1451330_a_at Inpp5b1.12 3.00E−10 6.14E−07 1424921_at Bst2 1.23 3.99E−10 7.83E−07 1419603_atIfi204 1.44 5.16E−10 9.70E−07 1438037_at Herc6 1.27 6.06E−10 1.09E−061419026_at Daxx 1.21 6.74E−10 1.7E−06

TABLE 17 15 probesets downregulated by Polimunol versus Copaxone ® Insplenocytes from Copaxone ®-immunized mice Probeset Gene raw.FC P.Valueadj.P.Val. 1454757_s_at Ifi27l1 −1.15 1.92E−08 1.57E−05 1415837_at Klk1−1.41 4.55E−08 3.16E−05 1452956_a_at Ifi27l1 −1.14 1.80E−07 9.56E−051448107_x_at Klk1 −1.34 2.21E−07 0.000114521 1439771_s_at D13ERTD608E−1.25 2.71E−07 0.00013591 1415823_at Scd2 −1.35 3.68E−06 0.0012756711442544_at Ighm −1.17 5.89E−06 0.001916738 1415824_at Scd2 −1.312.36E−05 0.006376176 1415822_at Scd2 −1.28 3.43E−05 0.0084898271429100_at Ccdc71l −1.08 3.68E−05 0.008965532 1427756_x_at Ighm −1.174.61E−05 0.010874062 1449325_at Fads2 −1.16 0.000104782 0.0222913631416188_at Gm2a −1.08 0.000109828 0.023255206 1424567_at Tspan2 −1.130.00016899 0.033873925 1436131_at Siglech −1.12 0.000216398 0.042416254

TABLE 18 Top 25 probesets upregulated by Polimunol versus Copaxone ® insplenocytes from Polimunol-immunized mice Probeset Gene raw.FC P.Valueadj.P.Val. 1434401_at Zcchc2 1.17 6.74E−14 1.96E−09 1417932_at Il18 1.268.67E−14 1.96E−09 1457035_at AI607873 1.43 1.41E−12 2.10E−081421551_s_at Ifi202b 1.43 1.86E−12 2.10E−08 1419599_s_at Ms4a6d 1.385.58E−12 5.04E−08 1456164_at AW011738 1.21 1.21E−11 9.11E−081457666_s_at Ifi202b /// 1.44 5.60E−11 2.73E−07 LOC100044068 1449591_atCasp4 1.11 6.06E−11 2.73E−07 1440865_at Ifitm6 1.23 7.78E−11 3.19E−071438004_at Papd7 1.19 9.92E−11 3.44E−07 1426721_s_at Tiparp 1.121.80E−10 5.81E−07 1426716_at Tdrd7 1.21 2.85E−10 8.56E−07 1419598_atMs4a6d 1.33 7.99E−10 2.17E−06 1420796_at Ahrr 1.47 1.38E−09 3.45E−061436058_at Rsad2 1.52 2.07E−09 4.67E−06 1421008_at Rsad2 1.40 2.22E−094.77E−06 1421009_at Rsad2 1.53 2.56E−09 5.07E−06 1418293_at Ifit2 1.422.58E−09 5.07E−06 1427102_at Slfn4 1.42 2.86E−09 5.38E−06 1453939_x_atGm9706 1.28 3.33E−09 6.02E−06 1427747_a_at Lcn2 1.21 3.54E−09 6.14E−061447851_x_at Atp10a 1.16 4.58E−09 7.37E−06 1450322_s_at Slfh3 /// Slfn41.38 5.25E−09 8.17E−06 1438148_at Cxcl3 1.68 6.34E−09 9.54E−061451905_a_at Mx1 1.79 1.09E−08 1.54E−05

TABLE 19 Top 25 probesets downregulated by Polimunol versus Copaxone ®in splenocytes from Polimunol-immunizad mice Probeset Gene raw.FCP.Value adj.P.Val. 1436839_at Ccdc71l −1.14 3.56E−11 2.11E−071451461_a_at Aldoc −1.60 3.75E−11 2.11E−07 1454757_s_at Ifi27l1 −1.159.61E−11 3.44E−07 1442544_at Ighm −1.29 8.19E−10 2.17E−06 1452956_a_atIfi27l1 −1.13 1.68E−09 3.99E−06 1417679_at Gfi1 −1.23 4.10E−09 6.85E−061417864_at Pgk1 −1.19 8.66E−09 1.26E−05 1429100_at Ccdc71l −1.121.45E−08 1.99E−05 1435086_s_at Klhdc2 −1.13 4.23E−08 4.33E−05 1451385_atFam162a −1.17 1.15E−07 0.000102062 1417034_at Trappc6a −1.18 1.33E−070.000111102 1435659_a_at Tpi1 −1.37 1.69E−07 0.000128996 1415995_atCasp6 −1.13 2.32E−07 0.000164607 1450081_x_at Gpi1 −1.13 3.06E−070.000206058 1434814_x_at Gpi1 −1.11 4.41E−07 0.000287936 1418709_atCox7a1 −1.31 4.64E−07 0.000298801 1417772_at Grhpr −1.23 4.84E−070.000307264 1439435_x_at Pgk1 −1.16 5.64E−07 0.000334169 1438640_x_atPgk1 −1.15 7.54E−07 0.00040969 1417308_at Pkm −1.14 1.00E−06 0.0005183151415918_a_at Tpi1 −1.31 1.08E−06 0.00055306 1424714_at Aldoc −1.321.23E−06 0.000599143 1418649_at Egln3 −1.27 1.29E−06 0.0006101231452927_x_at Tpi1 −1.29 1.34E−06 0.000631391 1457587_at Kcnq5 −1.141.86E−06 0.000789811

It is important to note that for either immunization (Copaxone® orPolimunol), I118 and its receptor I118r1 are downregulated (andinhibitor I118 bp is upregulated) by both of the activation treatments,Copaxone® and Polimunol. I118 is downregulated significantly less byPolimunol than by Copaxone® (differential expression FDR p<9e-6 (FC1.20) with Copaxone® immunization and FDR p<2e-9 (FC 1.26) for Polimunolimmunization). Downregulation of both I118 and I118r1 expression uponCopaxone® treatment was also reported in an earlier splenocyte study ofsimilar design (Bakshi et al, 2013). Boxplots of I118 expression areshown in FIG. 29.

The probesets significantly entiched among top probesets modulated byCopaxone® relative to medium is provided in Table 20.

TABLE 20 Top probesets significantly differentially expressed betweenPolimunol and Copaxone ® treatment (corrected for medium control) insplenocytes from Copaxone ®-immunized mice. Probeset Gene raw. FCAveExpr t P. Value adj. P. Val B 1421551_s_a Ifi202b 1.475509129.16666894 10.5600946 6.69E−15 3.02E−10 22.5317107 1451905_a_a Mx11.75432592 8.47709648 10.2249021 2.21E−14 4.98E−10 21.4748998 1421998_atTor3a 1.2928856 9.17160227 9.82507613 9.33E−14 1.40E−09 20.19322311457666_s_a Ifi202b /// L

1.49450011 8.60997589 9.74469879 1.25E−13 1.41E−09 19.9328881 1424339_atOasl1 1.46319835 9.8248556 9.60829298 2.05E−13 1.69E−09 19.4890911418293_at Ifit2 1.38359824 10.906172 9.5837092 2.24E−13 1.69E−0919.4088447 1423555_a_a Ifi44 1.62258196 9.94187992 9.51838876 2.85E−131.84E−09 19.1952407 1425917_at Ifi44l 1.6309207 8.85125178 8.798710724.06E−12 2.29E−08 16.8068255 1421596_s_a Ifi44l 1.62779642 8.550508428.4667453 1.40E−11 7.03E−08 15.6855236 1456164_at AW011738 1.197342346.98570845 8.33256611 2.32E−11 9.03E−08 15.2292395 1450454_at Tor3a1.25024933 8.74969803 8.32329605 2.40E−11 9.03E−08 15.1976556 1449455_atHck 1.1582816 10.9515022 8.18380999 4.06E−11 1.33E−07 14.72151391448775_at Gm16340 //

1.20618615 11.6014591 8.1770987 4.16E−11 1.33E−07 14.6985633 1438868_atPhf11d 1.2483759 10.329053 8.16092351 4.42E−11 1.33E−07 14.64323371428660_s_a Tor3a 1.248966 10.5033156 8.11568562 5.25E−11 1.41E−0714.488379 1434401_at Zcchc2 1.15603797 10.8249905 8.1125305 5.31E−111.41E−07 14.4775726 1418191_at Usp18 1.38861948 11.5218281 7.919697561.10E−10 2.71E−07 13.8156858 1450027_at Sdc3 1.25031078 10.45889387.9099888 1.14E−10 2.71E−07 13.7822905 1435331_at Pyhin1 1.1929209812.437413 7.74536994 2.12E−10 4.79E−07 13.2151145 1436120_at Setdb21.15959289 10.4269299 7.71019806 2.43E−10 5.21E−07 13.09371891451330_a_a Inpp5b 1.12122817 10.7773832 7.65452165 3.00E−10 6.14E−0712.90141 1424921_at Bst2 1.22915197 11.6875461 7.57865485 3.99E−107.83E−07 12.6390995 1419603_at Ifi204 1.43740773 7.15143963 7.510821045.16E−10 9.70E−07 12.4043263 1438037_at Herc6 1.27135334 10.44640577.46845772 6.06E−10 1.09E−06 12.2576026 1419026_at Daxx 1.2058658812.032791 7.44071108 6.74E−10 1.17E−06 12.1614627 1451567_a_a Gm16340 //

1.14843448 12.2623403 7.42376782 7.18E−10 1.20E−06 12.1027407 1426716_atTdrd7 1.17546145 9.81553185 7.38758714 8.24E−10 1.33E−06 11.97730911426774_at Parp12 1.23323427 10.568185 7.32082974 1.06E−09 1.60E−0611.7457533 1426276_at Ifih1 1.25213306 10.3259786 7.3202472 1.06E−091.60E−06 11.7437321 1435665_at Trim30d 1.25197418 9.71194292 7.268725281.29E−09 1.88E−06 11.5649255 1431591_s_a Gm9706 ///

1.32351255 11.382458 7.17864536 1.82E−09 2.56E−06 11.2521346 1435330_atPyhin1 1.20956064 9.18347439 7.12657207 2.22E−09 3.03E−06 11.07123641438716_at Trim30d 1.23305159 7.93829998 7.11825503 2.29E−09 3.03E−0611.0423392 1421008_at Rsad2 1.40087837 7.80703835 7.0280384 3.22E−094.15E−06 10.7288224 1421571_a_a Ly6c1 /// Ly6 1.12684658 13.6137526.99594752 3.64E−09 4.56E−06 10.6172805 1435792_at Csprs /// Gm 1.1874569.75936346 6.97563188 3.93E−09 4.76E−06 10.5466635 1423754_at Ifitm31.19002363 12.4964655 6.96462013 4.10E−09 4.76E−06 10.5083857 1457035_atAl607873 1.33928347 5.46136565 6.96314834 4.12E−09 4.76E−06 10.50326971453939_x_a Gm9706 1.28772667 8.70376747 6.95300697 4.28E−09 4.83E−0610.468017 1420671_x_a Ms4a4c 1.11351765 13.1959702 6.9122537 5.00E−095.50E−06 10.326351 1426721_s_a Tiparp 1.12038515 10.8883102 6.874043885.77E−09 6.20E−06 10.1935268 1427059_at Tmem184b 1.19049436 9.20535896.80169576 7.60E−09 7.97E−06 9.94204892 1453196_a_a Oasl2 1.3415130310.6174821 6.77476842 8.41E−09 8.62E−06 9.84846205 1452231_x_a Mndal1.20215669 12.1489677 6.75397715 9.10E−09 9.12E−06 9.77620711 1417932_atIl18 1.2024199 8.58526778 6.73898284 9.63E−09 9.44E−06 9.724101741420796_at Ahrr 1.35482305 6.39700067 6.68881415 1.16E−08 1.12E−059.54979119 1426906_at Mndal 1.22985583 12.0834069 6.68154198 1.20E−081.12E−05 9.52452794 1417244_a_a Irf7 1.29690765 11.8707637 6.664825921.28E−08 1.17E−05 9.46646104 1456494_a_a Trim30a ///

1.24228874 10.5953269 6.66073405 1.29E−08 1.17E−05 9.452247931445897_s_a Ifi35 1.09502194 13.2112571 6.64901185 1.35E−08 1.20E−059.41153295 1418115_s_a Tor1aip2 1.09066644 11.3826254 6.637876591.41E−08 1.22E−05 9.37285954 1426670_at Agrn 1.16650332 8.384647276.61334752 1.55E−08 1.32E−05 9.28767938 1450783_at Ifit1 1.3137042111.6154892 6.57611523 1.78E−08 1.49E−05 9.15841659 1436058_at Rsad21.44054736 10.0892795 6.52152657 2.19E−08 1.76E−05 8.96897228 1460603_atSamd9l 1.09852241 13.0008563 6.48452217 2.52E−08 1.99E−05 8.840610781450484_a_a Cmpk2 1.4069656 9.18452824 6.47037709 2.66E−08 2.06E−058.79155778 1452349_x_a Ifi205 /// Mn

1.20045125 7.72773058 6.46703491 2.69E−08 2.06E−05 8.77996877 1435529_atGm14446 1.28471375 11.9844626 6.46256796 2.74E−08 2.06E−05 8.764480311455581_x_a Gm20559 1.13805761 11.6732978 6.44922028 2.88E−08 2.09E−058.71820419 1451860_a_a Trim30a 1.18244967 12.1537452 6.36625749 3.94E−082.82E−05 8.43075121 1436562_at Ddx58 1.14667035 11.473735 6.361650424.00E−08 2.82E−05 8.41479807 1448380_at Lgals3bp 1.16298116 11.22441456.30367575 4.98E−08 3.40E−05 8.21414149 1449025_at Ifit3 1.341447811.8181697 6.30015076 5.05E−08 3.40E−05 8.20194708 1452087_at Epsti11.11549904 11.2912312 6.24845347 6.13E−08 4.01E−05 8.02318829 1421009_atRsad2 1.51117184 7.74253963 6.2035856 7.26E−08 4.64E−05 7.868179111443698_at Xaf1 1.18282113 11.9302802 6.20178329 7.30E−08 4.64E−057.86195528 1442130_at Hsh2d 1.1709592 10.2697537 6.16886582 8.27E−085.18E−05 7.7483219 1459151_x_a Ifi35 1.10594094 11.6543585 6.131359289.50E−08 5.87E−05 7.62066485 1436172_at Gm20559 1.1493816 11.53961116.07854249 1.16E−07 7.05E−05 7.43692632 1448575_at Il7r 1.0982543711.0940999 6.07547051 1.17E−07 7.05E−05 7.4263466 1452160_at Tiparp1.11979242 9.76721315 6.06904538 1.20E−07 7.13E−05 7.40422136 1451050_atNt5c3 1.16150561 10.6183063 6.05166841 1.28E−07 7.51E−05 7.344399911431095_a_a Herc6 1.19901119 10.4733187 6.04385458 1.32E−07 7.63E−057.31750846 1423681_at Ftsjd2 /// Rn

1.09083446 10.9815969 6.03884145 1.35E−07 7.68E−05 7.3002584 1449143_atRtp4 1.24304662 7.42935297 6.02268936 1.43E−07 8.05E−05 7.244694091437636_at Pydc4 1.33382761 8.19945237 6.01217359 1.49E−07 8.27E−057.20853136 1450495_a_a Klrk1 1.14444626 9.11777277 5.99801423 1.57E−078.59E−05 7.15985406 1450276_a_a Scin 1.26600893 8.7352575 5.994194561.59E−07 8.59E−05 7.14672584 1427091_at Znfx1 1.16622599 9.55031535.99232677 1.60E−07 8.59E−05 7.1403067 1432026_a_a Herc6 1.23325189.6340896 5.91285077 2.15E−07 0.00011289 6.86746993 1451777_at Ddx601.2572541 9.17655647 5.89999373 2.26E−07 0.00011573 6.823390161451655_at Slfn8 1.16818125 11.8030813 5.85259478 2.69E−07 0.000135916.6610318 1423071_x_a 6720475J19

1.12577119 8.9545691 5.84322799 2.79E−07 0.00013788 6.628975221450241_a_a Evi2a 1.11124373 11.3075457 5.84097845 2.81E−07 0.000137886.62127789 1421217_a_a Lgals9 1.11289495 12.0356748 5.83616937 2.86E−070.00013886 6.60482433 1424775_at Oas1a 1.26381284 10.9682776 5.829216612.94E−07 0.00014098 6.58104095 1447851_x_a Atp10a 1.13412363 9.357770395.81806601 3.06E−07 0.0001454 6.54290906 1451426_at Dhx58 1.2749423610.5332943 5.79964551 3.28E−07 0.00015407 6.47994653 1452013_at Atp10a1.16582075 7.25191599 5.74981475 3.95E−07 0.00018343 6.309816651438004_at Papd7 1.15866963 8.7651013 5.72747713 4.29E−07 0.000197226.23364804 1453757_at Herc6 1.25111898 9.09811412 5.64424695 5.83E−070.00026558 5.95039163 1456890_at Ddx58 1.20405595 8.33433728 5.639839715.93E−07 0.00026723 5.93541754 1416697_at Dpp4 1.1097733 9.721052765.63576616 6.01E−07 0.00026859 5.92157948 1422006_at Eif2ak2 1.234657299.21616067 5.61858421 6.41E−07 0.00028336 5.86323608 1424617_at Ifi351.10413772 12.2660487 5.60315363 6.78E−07 0.00029704 5.81087391426278_at Ifi27l2a 1.13356673 13.6135311 5.55624326 8.06E−07 0.000349645.65189199 1452676_a_a LOC1005051

1.11295467 9.74168879 5.53659908 8.67E−07 0.00037225 5.585410261451852_at Tcstv3 1.22404052 6.8712238 5.52210287 9.14E−07 0.000388915.53638704 1449366_at Mmp8 1.22832664 9.31371883 5.50428037 9.76E−070.00041133 5.47615784 1425405_a_a Adar 1.10728732 11.4786191 5.489968991.03E−06 0.0004295 5.42782879 1429570_at Mlkl 1.20072042 8.285237835.48602776 1.04E−06 0.00043175 5.4145249 1456288_at Slfn5 1.323402439.39871024 5.47997663 1.07E−06 0.00043504 5.3941035 1417961_a_a Trim30a1.17912824 12.8108758 5.47899844 1.07E−06 0.00043504 5.390802841444405_at Pydc4 1.32066484 5.20069324 5.43876125 1.24E−06 0.00049525.25516142 1435454_a_a Helz2 1.13249361 12.5204465 5.43239671 1.27E−060.00050243 5.23372972 1430530_s_a Nmral1 1.17435967 9.313559895.37375224 1.57E−06 0.00061706 5.03656379 1438148_at Cxcl3 1.690441937.09902456 5.35135811 1.71E−06 0.00065812 4.96142512 1422141_s_a Csprs/// Gm

1.19436756 7.71681771 5.33738357 1.80E−06 0.00068662 4.914580121418116_at Tor1aip2 1.08075944 10.7447031 5.32686698 1.87E−06 0.000707434.87934914 1425065_at Oas2 1.28607157 10.4532534 5.32376691 1.89E−060.0007095 4.86896748 1436778_at Cybb 1.1006634 12.2766584 5.290255392.13E−06 0.00079482 4.75685109 1428346_at Trafd1 1.15659445 11.26502295.28308824 2.19E−06 0.0008091 4.73289875 1440522_at Chic1 1.117076158.8938542 5.26963652 2.30E−06 0.00084269 4.68796879 1418580_at Rtp41.16283443 12.43898 5.25438045 2.43E−06 0.00088346 4.63705234 1425374_atOas3 1.32020993 10.3330288 5.23952375 2.56E−06 0.00092489 4.587510221435840_x_a BC147527 1.21647215 7.14546794 5.20034393 2.95E−060.00104904 4.45705855 1459913_at Tnfsf10 1.10617704 8.609820055.19467099 3.02E−06 0.00106241 4.43819454 1418346_at Insl6 1.13757758.67983728 5.17515811 3.24E−06 0.00113118 4.3733569 1440299_at Mb21d11.08850433 8.80638297 5.10764055 4.13E−06 0.0014208 4.149594181452306_at Zfyve26 1.08114798 10.6819271 5.09739051 4.28E−06 0.001462984.11570542 1425008_a_a Gm16340 //

1.14711446 8.2805057 5.07062975 4.71E−06 0.00159849 4.027332371426971_at Uba7 1.0921264 11.5979875 5.05902098 4.91E−06 0.001654043.98904342 1427102_at Slfn4 1.4307997 10.9094731 5.02506971 5.55E−060.00184054 3.87722913 1447272_s_a Atp10a 1.16573994 8.481467455.00861675 5.89E−06 0.00191674 3.82313389 1452161_at Tiparp 1.123415199.30889526 5.00763194 5.91E−06 0.00191674 3.81989785 1419668_at Sgcb1.11311815 8.08482712 4.99202128 6.25E−06 0.00201223 3.76863091452973_at Ppm1k 1.06538857 10.5472337 4.97566869 6.62E−06 0.002118083.71498595 1440866_st Eif2ak2 1.27644426 8.72230965 4.96189632 6.96E−060.00220906 3.66985249 1425225_at Fcgr4 1.15148701 7.97090773 4.949644947.27E−06 0.00229151 3.62973994 1428843_at 5-Mar 1.06276216 11.90043324.89939887 8.69E−06 0.00270208 3.46559327 1455500_at Rnf213 1.1810438812.9664015 4.8925931 8.90E−06 0.00273916 3.44340567 1450322_s_a Slfn3/// Slfn

1.32138137 7.84711588 4.8916997 8.93E−06 0.00273916 3.44049391419569_a_a Isg20 1.21173809 11.9296506 4.86452698 9.83E−06 0.002991613.35202465 1451161_a_a Emr1 1.18065879 9.48930222 4.86302162 9.88E−060.00299161 3.3471287 1452348_s_a Ifi204 /// Ifi2

1.22015123 10.6929234 4.85654465 1.01E−05 0.00304061 3.326069741451564_at Parp14 1.13986145 12.0654567 4.85172709 1.03E−05 0.003072423.31041282 1418244_at Naa20 1.08893101 11.1644701 4.76808963 1.38E−050.00407322 3.03951865 1436899_at Zufsp 1.09784747 11.1470022 4.748733541.48E−05 0.00433173 2.97708107 1419599_s_a Ms4a6d 1.33981893 8.571409964.74664377 1.49E−05 0.0043355 2.97034589 1443621_at Xaf1 1.165092947.24967566 4.74194912 1.51E−05 0.00437932 2.95521955 1436472_at Slfn91.11910501 8.38309804 4.73923193 1.53E−05 0.00439313 2.946467311453562_a_a Nmral1 1.15341413 9.19098832 4.73002801 1.58E−05 0.004508632.91683543 1454809_at Ncoa7 1.09311088 10.3983869 4.7257237 1.60E−050.00454843 2.90298546 1436779_at Cybb 1.0941996 11.6457179 4.71262361.68E−05 0.00473241 2.86086374 1426970_a_a Uba7 1.07523655 12.39846394.68910631 1.82E−05 0.00510655 2.78536262 1434139_at Parp11 1.0933875310.840668 4.6805127 1.88E−05 0.00522983 2.75781068 1452178_at Parp10 ///P

1.10641059 11.7358548 4.66046456 2.01E−05 0.00552329 2.69361311417516_at Ddit3 1.07223921 9.94848573 4.66039944 2.02E−05 0.005523292.69340478 1459973_x_a Dpp4 1.14507385 7.63353457 4.65962457 2.02E−050.00552329 2.69092573 1422140_at Gm7609 1.16864971 8.39169472 4.636090192.19E−05 0.00595944 2.61571222 1417685_at Ankfy1 1.06791545 11.09343384.61188057 2.39E−05 0.00640602 2.53850302 1423627_at Nqo1 1.164574756.67427154 4.59518149 2.53E−05 0.00674846 2.48534355 1451755_a_a Apobec11.07861266 9.62528811 4.56307937 2.83E−05 0.00749855 2.383376341430700_a_a Pla2g7 1.18443125 10.1013856 4.56135068 2.84E−05 0.007499452.37789398 1438948_x_a Tspo 1.10391642 11.5941786 4.5571403 2.89E−050.0075653 2.36454478 1450291_s_a Ms4a4c 1.12154489 12.4861899 4.554559722.91E−05 0.00758904 2.35636554 1419879_s_a Trim25 1.09549971 12.12443814.5525076 2.93E−05 0.00759918 2.34986266 1428615_at Lpar6 1.075283649.93379264 4.54743285 2.98E−05 0.00768686 2.33378681 1416695_at Tspo1.0780893 12.4808237 4.54588597 3.00E−05 0.00768686 2.328888131424857_a_a Trim34a 1.11791554 10.7165118 4.53973664 3.06E−05 0.007807632.30942125 1446457_at Ddx58 1.16007779 8.02122625 4.53347715 3.13E−050.00793348 2.28961716 1442640_at — 1.2168656 9.07831829 4.519295213.29E−05 0.00828496 2.24479093 1449078_at St3gal6 1.09165835 10.77275414.51684697 3.32E−05 0.0083088 2.23705863 1449591_at Casp4 1.1094822811.1338558 4.50971919 3.40E−05 0.00846848 2.2145572 1418030_at Slco3a11.08661497 9.54424904 4.49526041 3.57E−05 0.00880366 2.168959991416871_at Adam8 1.1193914 9.62857594 4.48900903 3.65E−05 0.008946242.14926531 1454668_at Ubr4 1.12814814 11.184894 4.48414411 3.71E−050.0089994 2.1339469 1442201_at — 1.1432126 9.81756401 4.479862463.77E−05 0.00908403 2.12047102 1436032_at — 1.21380001 11.13804934.47297003 3.86E−05 0.00925232 2.09878995 1454169_a_a Epsti1 1.1289733510.1539562 4.45618995 4.09E−05 0.00974916 2.04606725 1434601_at Amigo21.13289174 9.38089015 4.42595648 4.53E−05 0.01075628 1.951295941448576_at Il7r 1.10438001 9.35743301 4.3992231 4.96E−05 0.011662511.86773693 1421550_a_a Trim34a ///

1.12211108 9.72957463 4.39764723 4.99E−05 0.01166465 1.862818451415713_a_a Ddx24 1.06449185 11.5232541 4.37956906 5.31E−05 0.012342411.80645151 1419667_at Sgcb 1.12646472 8.33509646 4.34873052 5.90E−050.01363746 1.71054358 1455227_at Nceh1 1.08446292 9.91489676 4.340995636.05E−05 0.01392902 1.68653707 1418612_at Slfn1 1.09272571 12.964394.32568503 6.38E−05 0.01459714 1.63907653 1452318_a_a Hspa1b 1.190575387.25960902 4.30400323 6.86E−05 0.01562991 1.57200028 1427127_x_a Hspa1b1.21832745 7.30468517 4.29624366 7.04E−05 0.01588217 1.548033231419598_at Ms4a6d 1.30010562 8.68960331 4.29561853 7.06E−05 0.015882171.54610327 1448303_at Gpnmb 1.22944041 8.9049785 4.29482104 7.08E−050.01588217 1.54364139 1435660_at LOC664787 1.08388982 8.740338364.29173015 7.15E−05 0.01596949 1.5341017 1422511_a_a Ogfr 1.0723446812.3938197 4.24109747 8.48E−05 0.01875548 1.37829561 1437176_at Nlrc51.07682641 12.3735454 4.23387901 8.69E−05 0.01912232 1.356155361436633_at Gm11772 1.14601474 4.72784952 4.22090965 9.08E−05 0.019809881.316422 1451082_at Ftsjd2 /// R

1.06640728 11.3628274 4.2204656 9.09E−05 0.01980988 1.315062671425974_a_a Trim25 1.08480215 11.7657133 4.20895728 9.45E−05 0.020490281.27985683 1417876_at Fcgr1 1.2323332 7.0806629 4.19894373 9.77E−050.0210878 1.24926191 1457069_at Ascc3 1.11288948 9.43740297 4.195821279.87E−05 0.02120788 1.23972903 1429831_at Pik3ap1 1.06680759 12.47371434.1806008 0.0001039 0.0222095 1.19331067 1449538_a_a Gcnt1 1.119156178.47448492 4.14722631 0.00011614 0.02447684 1.09181994 1422005_atEif2ak2 1.19563857 9.53538322 4.12771094 0.00012393 0.025996981.03266263 1449875_s_a H2-T10 /// H

1.04842787 12.8867189 4.11331035 0.00013 0.02714397 0.989099951418722_at Ngp 1.11092189 12.7881149 4.10510418 0.00013359 0.027764290.96431022 1426133_a_

Mitd1 1.10636222 10.1667831 4.07764709 0.00014629 0.03009875 0.881549441424354_at Tmem140 1.11754478 9.34810202 4.07577197 0.0001472 0.030098750.87590785 1423052_at Arf4 1.05369833 12.3484921 4.06902312 0.000150520.03046771 0.85561388 1456251_x_a Tspo 1.1023499 11.1159008 4.068774180.00015065 0.03046771 0.85486562 1423986_a_a Shisa5 1.0421081314.2786011 4.03888346 0.00016625 0.03347242 0.76519512 1428378_atZc3hav1 1.08752006 10.7288018 4.02875397 0.00017188 0.0343001 0.734885081420401_a_a Ramp3 1.12512462 9.98404572 4.00377593 0.00018656 0.03706680.66031463 1460657_at Wnt10a 1.12684061 8.35987776 3.98317991 0.000199580.03947847 0.59901024 1424444_a_a 1600014C10

1.09898446 11.5959589 3.98018984 0.00020154 0.03969221 0.590124181428444_at Asb2 1.13292232 8.24932226 3.95719355 0.00021725 0.042416250.52190117 1439814_at Atp8b4 1.11510444 9.33960673 3.95146957 0.000221340.04302868 0.50495269 1429588_at 2810474O19

1.05637397 11.2428969 3.93455457 0.00023387 0.04526887 0.45494511433617_s_a B4galt5 1.11846333 10.5599476 3.92169381 0.000243850.04679878 0.41700096 1431296_at Gpr15 1.14301562 6.60205175 3.91932650.00024573 0.04695995 0.41002381 1454757_s_a Ifi27l1 −1.151524911.2428344 −6.5569053 1.92E−08 1.57E−05 9.09173948 1415837_at Klk1−1.4082454 7.5804401 −6.3275656 4.55E−08 3.16E−05 8.29680484 1452956_a_aIfi27l1 −1.1424326 10.7927481 −5.9606126 1.80E−07 9.56E−05 7.031361781448107_x_a Klk1 −1.3445567 7.49119412 −5.9058876 2.21E−07 0.000114526.84359495 1439771_s_a D13ERTD608

−1.2546842 8.86787505 −5.8507689 2.71E−07 0.00013591 6.654782121415823_at Scd2 −1.3537166 10.2235672 −5.1396945 3.68E−06 0.001275674.25571056 1442544_at Ighm −1.1737796 9.42424035 −5.0083987 5.89E−060.00191674 3.82241733 1415824_at Scd2 −1.3093243 10.9433795 −4.61494112.36E−05 0.00637618 2.54825457 1415822_at Scd2 −1.2780512 11.8313256−4.5073901 3.43E−05 0.00848983 2.20720796 1429100_at Ccdc71l −1.084935710.7147161 −4.4868075 3.68E−05 0.00896553 2.14233223 1427756_x_a Ighm−1.1707153 9.14115987 −4.4212385 4.61E−05 0.01087406 1.936532671449325_at Fads2 −1.1644392 8.52583689 −4.1780844 0.00010478 0.022291361.18564443 1416188_at Gm2a −1.0836296 10.9313169 −4.163994 0.000109830.02325521 1.1427593 1424567_at Tspan2 −1.1339633 9.59951853 −4.03390510.00016899 0.03387392 0.75029377 1436131_at Siglech −1.12487757.91450702 −3.9583983 0.0002164 0.04241625 0.52546999

indicates data missing or illegible when filed

Polimunol and Copaxone® Comparison: Differentially Expressed Pathways,Under Copaxone® Immunization

After imposing a conservative fold change filter of |FC|≧1.2, 73probesets are found to be upregulated by Polimunol relative to Copaxone®(medium-corrected, in Copaxone®-immunized mice), and these probesetsenrich for 22 pathways, including immune response and response to virus.These pathways may be relevant to Copaxone's mechanism of action;several of these pathways are also enriched among probesets modulated byCopaxone® relative to control (e.g., immune response and immune systemprocess). A total of 6 downregulated probesets are detected, which donot enrich for pathways. The upregulated pathways are depicted in FIG.30 and the full list of pathways enriched among top probesetsupregulated by Polimunol relative to Copaxone® is provided in Table 21.

TABLE 21 Pathways enriched among top probesets upregulated by Polimunolrelative to Copaxone ® (in Copaxone ® -immunized mice). Category TermCount Pvalue Fold Enrichm Benjamini GOTERM_BP_ALL GO: 0006955~immuneresponse 15 4.38E−11 9.95074106 1.98E−08 GOTERM_BP_ALL GO:0009615~response to virus 8 8.16E−10 38.2602137 1.84E−07 GOTERM_BP_ALLGO: 0002376~immune system process 15 8.29E−08 5.57817311 9.35E−06GOTERM_BP_ALL GO: 0051707~response to other organism 9 8.19E−0814.9261116 1.23E−05 GOTERM_BP_ALL GO: 0050896~response to stimulus 211.38E−07 3.37128932 1.25E−05 GOTERM_BP_ALL GO: 0009607~response tobiotic stimulus 9 1.27E−06 10.4567109 9.54E−05 GOTERM_BP_ALL GO:0051704~multi-organism process 9 1.63E−06 10.113868 0.00010525KEGG_PATHWAY mmu04622: RIG-1-like receptor signaling pathway 5 1.47E−0527.2429078 0.00023467 KEGG_PATHWAY mmu04623: Cytosolic DNA-sensingpathway 4 0.00031378 25.6083333 0.00250745 GOTERM_BP_ALL GO:0045087~innate immune response 5 0.00030987 14.6891892 0.01731968GOTERM_MF_ALL GO: 0001882~nucleoside binding 16 0.00118891 2.411120970.02621825 GOTERM_MF_ALL GO: 0032559~adenyl ribonucleotide binding 160.00065908 2.54969114 0.02901942 GOTERM_MF_ALL GO: 0001883~purinenucleoside binding 16 0.00112323 2.42429649 0.02967043 GOTERM_BP_ALL GO:0006952~defense response 7 0.00060685 6.34158828 0.02996091GOTERM_MF_ALL GO: 0030554~adenyl nucleotide binding 16 0.001060692.4376168 0.03492727 GOTERM_MF_ALL GO: 0032553~ribonucleotide binding 170.00211744 2.18735104 0.03976457 GOTERM_MF_ALL GO: 0032555~purineribonucleotide binding 17 0.00211744 2.18735104 0.03976457 GOTERM_MF_ALLGO: 0005524~ATP binding 16 0.00061962 2.56442924 0.04067708GOTERM_MF_ALL GO: 0001730~2′-5′-oligoadenylate synthetase activity 30.0003357 99.8204082 0.04399453 GOTERM_MF_ALL GO: 0017076~purinenucleotide binding 17 0.00310625 2.1090566 0.04526422 GOTERM_MF_ALL GO:0016779~nucleotidyltransferase activity 5 0.00284393 8.236007270.04658368 GOTERM_MF_ALL GO: 0003723~RNA binding 10 0.003714173.08659271 0.04863977

Polimunol/Copaxone® Comparison: Differentially Expressed Pathways,Polimunol Immunization

In Polimunol-immunized mice, after imposing a fold change filter of|FC|≧1.2, 77 probesets are upregulated by Polimunol relative toCopaxone® (medium-corrected, in Polimunol-immunized mice), and theseprobesets enrich for 10 pathways. These pathways are similar to thoseseen in the comparison for Copaxone®-immunized mice, and includepathways relevant to Copaxone's mechanism of action such as immuneresponse and immune system process pathways, as well as potentiallyconcerning pathways such as response to virus. 22 downregulatedprobesets are detected, which do not enrich for pathways. Theupregulated pathways are depicted in FIG. 31 and provided in Table 22.

TABLE 22 Pathways enriched among top probesets upregulated by Polimunolrelative to Copaxone ® (in Polimunol-immunized mice). Category TermCount Pvalue Fold Enrichm Benjamini GOTERM_BP_ALL GO: 0009615~responseto virus 8 3.62E−09 31.4583979 1.93E−06 GOTERM_BP_ALL GO:0009607~response to biotic stimulus 11 4.50E−08 10.508349 1.20E−05GOTERM_BP_ALL GO: 0051707~response to other organism 9 4.30E−0712.2725806 5.73E−05 GOTERM_BP_ALL GO: 0050896~response to stimulus 233.87E−07 3.03594414 6.88E−05 GOTERM_BP_ALL GO: 0051704~multi-organismprocess 10 7.59E−07 9.23982999 8.09E−05 GOTERM_BP_ALL GO: 0006955~immuneresponse 12 9.89E−07 6.54537634 8.78E−05 GOTERM_BP_ALL GO:0002376~immune system process 12 0.0002277 3.66919831 0.01719059GOTERM_CC_ALL GO: 0044421~extracellular region part 7 0.000987545.86744639 0.03589677 GOTERM_CC_ALL GO: 0005576~extracellular region 100.00051394 4.06619385 0.03732702 GOTERM_CC_ALL GO: 0005615~extracellularspace 6 0.00178939 6.62813102 0.04321627

Polimunol and Copaxone Comparison: Discussion

The fact that Polimunol modulates IL18 to a significantly differentextent than Copaxone®, consistently, regardless of immunization agent isnoteworthy and has potential implications for both safety and efficacy.IL18 is important for T helper cell differentiation, and IL18 levels arehigher in serum from MS patients versus controls, as well as acuteversus stable MS (Nicoletti et al, 2001). The signaling pathway forIL-18 appears in FIG. 32a . IL18 also induces IFNg expression and hasbeen implicated in MS immunopathogenesis (Losy et al, 2001). IL18genetic variants have further been shown to affect MS risk (Celik et al,2014; Thompson et al, 2007). Moreover, mice deficient for IL18 areresistant to EAE (Shi et al, J. Immunol., 2000) as shown in FIG. 32 b.

Intriguingly, a number of interferon-related genes are upregulated byPolimunol relative to Copaxone® in this model system. FIG. 33 showsillustrated pathways of IFN Type I production (Trinchieri et al, J ExpMed, 2010), with overlay indicating genes including RIG-I, MDA5, andIRF7 upregulated by Polimunol versus Copaxone. As the figure indicates,the upregulation of these genes would be consistent with an increase intype I interferon production.

At the pathway level, the fact that a variety of immune-related pathwaysare enriched among the differentially expressed probesets, including“immune system process” and “response to virus,” and that differentialexpression is seen for multiple genes affecting interferon signaling(e.g. leading to the significant enrichment of the RIG-I-like receptorsignaling pathway in the comparison between Polimunol and Copaxone® inCopaxone-immunized mice), raises serious concerns for safety andefficacy.

Example 11 Differences in Gene Expression Induced by Polimunol VersusBranded GA in Human Monocyte (THP-1) Gene Expression Studies

The immunized mouse splenocyte model system has proved robust andinformative in examining Copaxone®'s mode of action, as well as indifferentiating between seemingly similar FOGAs and Copaxone® [Bakshi etal, 2013; Towfic et al, 2014; FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein; and FDA-2013-P-1641-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2013-P-1641-000l, and alsodescribed herein. To follow up on these findings and test a human-sourcemodel system, THP-1 cells were utilized. The research community usesthis human monocyte cell line to model the behavior ofantigen-presenting cells. As described in further detail in the methodssection below, THP-1 cells were utilized to (1) compare the genome-widetranscriptional impact of Copaxone® to that of a mannitol control, inorder to shed additional light on Copaxone®'s mechanism of action (MoA),and to (2) compare the genome-wide transcriptional impact of Copaxone®to that of purported generics, including Polimunol. It is critical tomethodologically pursue the MoA analyses first and independently of anysubsequent investigations so as to ensure the validity and robustness ofeach experiment. To this end, at least three different batches ofCopaxone are tested and analyzed in comparison to control and to priorsimilar studies.

The study was performed in two repeats identical in design, reagents,drug lots, and technicians, performed on different days. Six replicatesamples for each condition were utilized in each of the two experimentalruns for a total of twelve replicates per condition, making this studywell powered to detect changes in expression levels across conditions.

Copaxone®-Modulated Genes (MoA)

Copaxone® significantly upregulated 5296 probesets, and significantlydownregulated 6819 probesets, out of >25,000 probesets called present onthe chip. Consistent with previous studies (e.g. FDA-2014-P-0933-0001available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein), the anti-inflammatory gene IL1RN was stronglyupregulated by Copaxone® (all 3 IL1RN probesets that were called presentin the study: FDR p values<6.2e-21, 2.6e-17, 8.0e-14); see FIG. 34a -c.

IL10 was not upregulated significantly, but may have been difficult todetect because the single probeset on the chip was not present. IL1ORA,representing the receptor necessary for IL10 signaling, wassignificantly upregulated (FDR p<1.7e-21), indicating this pathwayupregulated by Copaxone®, as expected. These results are consistent withthe results of a prior study presented earlier, of which the currentlydiscussed data represents two independent confirmatory datasets(FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein).

To test concordance with previous observations in the same model system,sets of top probesets modulated by Copaxone® were defined based on twoprior THP-1 studies (FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein), by taking the intersection of the top probesets(subject to fold change (FC) filter of 1.5, treating up anddownregulated probesets separately) modulated by Copaxone® across bothprior datasets (see Table 23). Significant enrichment of these sets bydirectionality was found in the present dataset among probesetsupregulated by Copaxone® versus mannitol (FC≧1.5) and probesetsdownregulated by Copaxone® versus mannitol (FC≦−1.5) by thehypergeometric test: 2.4e-10 and 7.6e-11 for up and downregulated sets,respectively.

TABLE 23 Top probesets modulated by Copaxone ® are significantlyenriched among the top probesets modulated by Copaxone ® in prior THP-1studies. In two prior In current THP-1 studies study IntersectionProbesets upregulated by 149 156 94 Copaxone versus mannitol with FC ≧1.5 Probesets downregulated 15 28 9 by Copaxone versus mannitol with FC≦ −1.5

Copaxone®-Modulated Pathways

Among the top probesets upregulated by Copaxone® with FC≧1.3, 180pathways were enriched. This includes immune response, immune systemprocess, and cytokine-cytokine receptor interaction and regulation of Bcell activation (as observed in prior THP-1 studies, e.g.FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein) as well as coagulation, positive regulation oflymphocyte activation and proliferation, and positive regulation ofB-cell activation and proliferation. The full list of pathways entichedamong top probesets differentially expressed by Copaxone® relative tomannitol control in THP-1 cells is provided in Table 24.

TABLE 24 Pathways significantly enriched among top probesets differentlyexpressed by Copaxone ® relative to mannitol control in THP-1 cells.Category Term Count Pvalue Fold Enrichm Benjamini DOWN GOTERM_BP_ALL GO:0048513~organ development 30 2.78E−06 2.52785617 0.00198109GOTERM_BP_ALL GO: 0032502~developmental process 44 2.37E−06 1.993222390.00337678 GOTERM_BP_ALL GO: 0048856~anatomical structure development 361.55E−05 2.07315026 0.00550192 GOTERM_BP_ALL GO: 0016337~cell-celladhesion 10 1.38E−05 6.80689385 0.00654548 GOTERM_BP_ALL GO:0048731~system development 33 3.08E−05 2.11219642 0.00874514GOTERM_BP_ALL GO: 0007275~multicellular organismal development 378.63E−05 1.88932377 0.0203102 UP GOTERM_CC_ALL GO: 0005886~plasmamembrane 122 2.34E−25 2.51413927 5.85E−23 GOTERM_CC_ALL GO:0031226~intrinsic to plasma membrane 58 6.43E−19 3.81223099 8.04E−17GOTERM_BP_ALL GO: 0009611~response to wounding 44 2.00E−19 3.21029732.16E−16 GOTERM_BP_ALL GO: 0009605~response to external stimulus 581.09E−19 3.93471319 2.34E−16 GOTERM_BP_ALL GO: 0050896~response tostimulus 118 6.20E−19 2.15982642 4.45E−16 GOTERM_CC_ALL GO:0005887~integral to plasma membrane 56 7.55E−18 3.73686273 6.29E−16GOTERM_BP_ALL GO: 0006955~immune response 46 7.16E−17 4.268938 4.79E−14GOTERM_BP_ALL GO: 0002376~immune system process 59 7.00E−17 3.378238035.97E−14 GOTERM_CC_ALL GO: 0016020~membrane 174 1.26E−14 1.560613766.33E−13 GOTERM_CC_ALL GO: 0005576~extracellular region 58 1.03E−143.10216639 6.45E−13 GOTERM_BP_ALL GO: 0006932~defense response 401.08E−14 4.30462838 3.86E−12 GOTERM_CC_ALL GO: 0044439~plasma membranepart 76 9.39E−14 2.43596934 4.00E−12 GOTERM_MF_ALL GO:0004888~transmembrane receptor activity 39 4.19E−14 4.23233219 8.19E−12GOTERM_MF_ALL GO: 0060089~molecular transducer activity 69 3.91E−142.64236631 1.15E−11 GOTERM_MF_ALL GO: 0004871~signal transducer activity69 3.91E−14 2.64356631 1.15E−11 GOTERM_MF_ALL GO: 0004872~receptoractivity 56 3.49E−14 3.09677878 2.05E−11 GOTERM_CC_ALL GO:0044421~extracellular region part 37 1.44E−12 4.00069218 3.16E−11GOTERM_BP_ALL GO: 0006934~inflammatory response 28 1.16E−12 5.378282783.57E−10 GOTERM_CC_ALL GO: 0031234~intrinsic to membrane 125 9.85E−111.63813557 3.08E−09 GOTERM_CC_ALL GO: 0016021~integral to membrane 1212.99E−10 1.63586081 8.31E−09 GOTERM_CC_ALL GO: 0044425~membrane part 1461.37E−09 1.49687764 3.43E−08 KEGG_PATHWAY hsa04060: Cytokine-cytokinereceptor interaction 21 4.90E−10 3.38268996 5.00E−08 GOTERM_CC_ALL GO:0005615~extracellular space 27 2.52E−09 4.02507822 5.72E−08GOTERM_BP_ALL GO: 0006930~response to stress 70 5.34E−10 2.131485341.44E−07 GOTERM_BP_ALL GO: 0042060~wound healing 19 7.93E−10 6.277224331.90E−07 GOTERM_BP_ALL GO: 0050793~regulation of developmental process38 9.55E−10 3.11524781 2.06E−07 GOTERM_BP_ALL GO: 0031501~multicellularorganismal process 103 1.58E−09 1.72386846 3.09E−07 GOTERM_BP_ALL GO:0031239~regulation of multicellular organismal process 43 2.23E−092.76388129 4.03E−07 GOTERM_BP_ALL GO: 0048731~system development 742.51E−09 1.99902 4.15E−07 GOTERM_BP_ALL GO: 0048314~blood vesselmorphogenesis 20 5.89E−09 5.24413041 9.07E−07 GOTERM_BP_ALL GO:0048383~regulation of response to stimulus 29 6.99E−09 3.588399489.41E−07 GOTERM_BP_ALL GO: 0040011~locomotion 27 6.77E−09 3.828440419.71E−07 GOTERM_BP_ALL GO: 0007165~signal transduction 79 1.11E−081.87343671 1.40E−06 GOTERM_BP_ALL GO: 0001568~blood vessel development21 1.27E−08 4.73204438 1.52E−06 GOTERM_BP_ALL GO: 0001944~vasculaturedevelopment 21 1.61E−08 4.68782736 1.82E−06 GOTERM_MF_ALL GO:0019933~cytokine binding 14 1.61E−08 7.82935604 2.36E−06 GOTERM_BP_ALLGO: 0065008~regulation of biological quality 55 3.55E−08 2.181382063.82E−06 GOTERM_BP_ALL GO: 0001525~angiogenesis 16 6.27E−08 5.873426286.43E−06 GOTERM_BP_ALL GO: 0048856~anatomical structure development 759.87E−08 1.82463307 9.66E−06 GOTERM_BP_ALL GO: 0002682~regulation ofimmune system process 23 1.35E−07 3.52970329 1.26E−05 GOTERM_CC_ALL GO:0009986~cell surface 20 6.73E−07 3.93630209 1.40E−05 GOTERM_BP_ALL GO:0007275~multicellular organismal development 80 3.39E−07 1.724097733.04E−05 GOTERM_BP_ALL GO: 0048513~organ development 56 5.42E−071.99152773 4.67E−05 GOTERM_BP_ALL GO: 0032502~developmental process 867.67E−07 1.64425345 6.11E−05 GOTERM_BP_ALL GO: 0048584~positiveregulation of response to stimulus 18 7.65E−07 4.30930732 6.33E−05GOTERM_BP_ALL GO: 0002684~positive regulation of immune system process18 8.48E−07 4.27830511 6.52E−05 GOTERM_BP_ALL GO: 0016477~cell migration19 1.39E−06 3.92326521 0.00010335 GOTERM_BP_ALL GO: 0048318~positiveregulation of biological process 70 1.76E−06 1.74540498 0.00012637GOTERM_BP_ALL GO: 0048519~negative regulation of biological process 652.99E−06 1.77184118 0.00020737 GOTERM_BP_ALL GO: 0032101~regulation ofresponse to external stimulus 13 3.24E−06 5.50633714 0.00021167GOTERM_BP_ALL GO: 0007168~cell surface receptor linked signaltransduction 43 3.17E−06 2.13308554 0.00021349 GOTERM_BP_ALL GO:0048870~cell motility 19 3.65E−06 3.67089141 0.00023142 GOTERM_BP_ALLGO: 0051674~localization of cell 19 3.65E−06 3.67089142 0.00023142GOTERM_BP_ALL GO: 0051707~response to other organism 18 3.91E−063.83667362 0.00024052 GOTERM_CC_ALL GO: 0031012~extracellular matrix 141.81E−05 4.34038261 0.00034771 GOTERM_BP_ALL GO: 0050878~regulation ofbody fluid levels 12 5.88E−06 5.7457431 0.00035133 GOTERM_BP_ALL GO:0006928~cell motion 24 6.70E−06 2.92587656 0.00038982 GOTERM_BP_ALL GO:0050776~regulation of immune response 16 7.15E−06 4.09773926 0.00040481GOTERM_BP_ALL GO: 0042127~regulation of cell proliferation 34 8.23E−062.32085284 0.00043212 GOTERM_BP_ALL GO: 0022603~regulation of anatomicalstructure morphogenesis 16 7.86E−06 4.06621819 0.000434 GOTERM_BP_ALLGO: 0042330~taxis 13 8.15E−06 5.05287408 0.00043846 GOTERM_BP_ALL GO:0006935~chemotaxis 13 8.15E−06 5.05287408 0.00043846 GOTERM_BP_ALL GO:0048646~anatomical structure formation involved in 21 8.68E−063.18256183 0.00044506 morphogenesis GOTERM_BP_ALL GO: 0065007~biologicalregulation 170 9.39E−06 1.25760499 0.00046996 GOTERM_BP_ALL GO:0042221~response to chemical stimulus 47 1.17E−05 1.94341311 0.00057284GOTERM_BP_ALL GO: 0002703~regulation of leukocyte mediated immunity 91.37E−05 7.82479488 0.00064059 GOTERM_BP_ALL GO: 0007626~locomotorybehavior 16 1.37E−05 3.88682621 0.00065406 GOTERM_BP_ALL GO:0050865~regulation of cell activation 14 1.49E−05 4.40506971 0.00068044GOTERM_MF_ALL GO: 0019838~growth factor binding 11 5.88E−06 6.464431980.00069034 GOTERM_BP_ALL GO: 0002822~regulation of adaptive immuneresponse based on 9 1.68E−05 7.62415911 0.00075234 somatic recombinationof immune receptors built from immunoglobulin superfamily domainsGOTERM_BP_ALL GO: 0002819~regulation of adaptive immune response 92.04E−05 7.43355513 0.0008974 GOTERM_BP_ALL GO: 0030154~celldifferentiation 49 2.72E−05 1.848017258 0.00116853 GOTERM_BP_ALL GO:0048522~positive regulation of cellular process 62 3.31E−05 1.674862970.00139553 GOTERM_BP_ALL GO: 0050789~regulation of biological process162 3.82E−05 1.2502125 0.00158231 GOTERM_BP_ALL GO: 0010033~response toorganic substance 31 4.31E−05 2.24600094 0.00171764 GOTERM_BP_ALL GO:0008284~positive regulation of cell proliferation 21 4.26E−05 2.855137770.00172889 GOTERM_BP_ALL GO: 0045765~regulation of angiogenesis 84.56E−05 8.00921765 0.00178429 GOTERM_BP_ALL GO: 0050867~positiveregulation of cell activation 11 4.77E−05 5.11856691 0.00183348GOTERM_CC_ALL GO: 0005578~proteinaceous extracellular matrix 120.0001102 4.24643494 0.00196599 GOTERM_CC_ALL GO: 0031982~vesicle 280.00012722 2.234456653 0.00211822 GOTERM_BP_ALL GO: 0048869~cellulardevelopmental process 50 5.94E−05 1.77814977 0.00220286 GOTERM_BP_ALLGO: 0048545~response to steroid hormone stimulus 13 5.85E−05 4.169847540.00220693 GOTERM_BP_ALL GO: 0051094~positive regulation ofdevelopmental process 17 6.39E−05 3.24651091 0.00232928 GOTERM_BP_ALLGO: 0032879~regulation of localization 25 0.00010654 2.40101910.00381602 GOTERM_CC_ALL GO: 0016023~cytoplasmic membrane-boundedvesicle 24 0.0002448 2.32906958 0.00381824 KEGG_PATHWAY hsa04640:Hematopoietic cell lineage 9 8.02E−05 6.02036055 0.00408452GOTERM_CC_ALL GO: 0009897~external side of plasma membrane 10 0.000316484.54973171 0.00464398 GOTERM_CC_ALL GO: 0031988~membrane-bounded vesicle24 0.00039301 2.25413972 0.00490148 GOTERM_CC_ALL GO: 0030141~secretorygranule 11 0.00038339 4.01420803 0.00503284 GOTERM_CC_ALL GO:0031410~cytoplasmic vesicle 26 0.00037285 2.16871498 0.00516605GOTERM_BP_ALL GO: 0015718~monocarboxylic acid transport 7 0.000152898.2595057 0.00538215 GOTERM_BP_ALL GO: 0048523~negative regulation ofcellular process 56 0.00015724 1.64309882 0.00544596 GOTERM_BP_ALL GO:0002696~positive regulation of leukocyte activation 10 0.000166184.93104818 0.00566357 GOTERM_BP_ALL GO: 0002694~regulation of leukocyteactivation 12 0.00018259 4.00460883 0.00612434 GOTERM_BP_ALL GO:0050864~regulation of B cell activation 7 0.00018795 7.974695160.00620684 GOTERM_BP_ALL GO: 0050871~positive regulation of B cellactivation 6 0.00019715 10.4330598 0.00641133 GOTERM_BP_ALL GO:0042981~regulation of apoptosis 35 0.00020205 1.94996762 0.00647234GOTERM_BP_ALL GO: 0051240~positive regulation of multicellularorganismal process 14 0.00020826 3.42616532 0.00657273 GOTERM_BP_ALL GO:0007186~G-protein coupled receptor protein signaling pathway 190.00021787 2.70570014 0.00677572 GOTERM_BP_ALL GO: 0030890~positiveregulation of B cell proliferation 5 0.00022555 15.0172831 0.00691393GOTERM_BP_ALL GO: 0043067~regulation of programmed cell death 350.00024393 1.93043539 0.00737064 GOTERM_BP_ALL GO:0051704~multi-organism process 28 0.00024768 2.14135333 0.00737981GOTERM_BP_ALL GO: 0080134~regulation of response to stress 16 0.000252253.02061929 0.00741299 GOTERM_BP_ALL GO: 0009653~anatomical structuremorphogenesis 38 0.00025614 1.85991832 0.00742555 GOTERM_BP_ALL GO:0010941~regulation of cell death 35 0.00026015 1.92401131 0.00744133GOTERM_BP_ALL GO: 0045087~innate immune response 10 0.000290114.58861428 0.00808025 GOTERM_BP_ALL GO: 0001501~skeletal systemdevelopment 15 0.00028723 3.13652115 0.00810512 GOTERM_BP_ALL GO:0050794~regulation of cellular process 153 0.00029774 1.227493320.00818597 GOTERM_BP_ALL GO: 0007155~cell adhesion 23 0.000355992.31669062 0.0096566 GOTERM_BP_ALL GO: 0022610~biological adhesion 230.0003765 2.30964901 0.01008332 GOTERM_BP_ALL GO: 0002706~regulation oflymphocyte mediated immunity 7 0.00039607 7.00806545 0.01047439GOTERM_BP_ALL GO: 0002697~regulation of immune effector process 90.00040369 4.95570342 0.01054539 GOTERM_BP_ALL GO: 0032680~regulation oftumor necrosis factor production 6 0.00041457 9.01036985 0.0106985GOTERM_BP_ALL GO: 0051270~regulation of cell motion 13 0.000433383.38184485 0.01104886 GOTERM_BP_ALL GO: 0009607~response to bioticstimulus 18 0.00048671 2.61975511 0.01225545 GOTERM_BP_ALL GO:0048878~chemical homeostasis 19 0.00051554 2.52097362 0.01282688GOTERM_BP_ALL GO: 0051241~negative regulation of multicellularorganismal process 10 0.00053115 4.23564395 0.01306189 GOTERM_BP_ALL GO:0031099~regeneration 7 0.00055185 6.60760456 0.01341453 GOTERM_BP_ALLGO: 0001503~ossification 9 0.00056526 4.71971754 0.01358496GOTERM_BP_ALL GO: 0007596~blood coagulation 8 0.00060782 5.393962910.01443964 GOTERM_BP_ALL GO: 0050817~coagulation 8 0.00060782 5.393962910.01443964 GOTERM_BP_ALL GO: 0051251~positive regulation of lymphocyteactivation 9 0.00062947 4.64597198 0.01478703 GOTERM_BP_ALL GO:0030193~regulation of blood coagulation 5 0.00063688 11.79929380.01479853 GOTERM_BP_ALL GO: 0046903~secretion 14 0.00066151 3.042975790.01520272 GOTERM_BP_ALL GO: 0060348~bone development 9 0.000699434.57449547 0.0158979 GOTERM_BP_ALL GO: 0002700~regulation of productionof molecular mediator of 6 0.00077675 7.92912548 0.01745622 immuneresponse GOTERM_BP_ALL GO: 0030888~regulation of B cell proliferation 50.00084803 11.0126743 0.01846594 GOTERM_BP_ALL GO: 0050778~positiveregulation of immune response 10 0.00083992 3.98048468 0.01847785GOTERM_BP_ALL GO: 0010876~lipid localization 11 0.00083164 3.634182510.01848608 GOTERM_BP_ALL GO: 0001819~positive regulation of cytokineproduction 9 0.00085816 4.43794336 0.01849764 GOTERM_BP_ALL GO:0032103~positive regulation of response to external stimulus 7 0.00087026.08595157 0.01856902 GOTERM_BP_ALL GO: 0007610~behavior 17 0.000888882.57635958 0.01877795 GOTERM_BP_ALL GO: 0051179~localization 800.00090886 1.39180717 0.01900988 GOTERM_CC_ALL GO: 0031091~plateletalpha granule 6 0.0016609 6.78059772 0.01959452 GOTERM_BP_ALL GO:0009615~response to virus 9 0.00094771 4.37267949 0.01962413GOTERM_BP_ALL GO: 0043065~positive regulation of apoptosis 22 0.000971042.20253485 0.01972357 GOTERM_BP_ALL GO: 0001817~regulation of cytokineproduction 12 0.00096317 3.30380228 0.01975149 GOTERM_BP_ALL GO:0015849~organic acid transport 10 0.00099852 3.88682621 0.02008682GOTERM_BP_ALL GO: 0046942~carboxylic acid transport 10 0.000998523.88682621 0.02008682 GOTERM_BP_ALL GO: 0007167~enzyme linked receptorprotein signaling pathway 16 0.00103032 2.64304183 0.02052865GOTERM_BP_ALL GO: 0043068~positive regulation of programmed cell death22 0.00104554 2.18926657 0.02063801 GOTERM_BP_ALL GO: 0010942~positiveregulation of cell death 22 0.0010885 2.1826922 0.02128235 GOTERM_BP_ALLGO: 0007599~hemostasis 8 0.00110252 4.8945219 0.02135976 GOTERM_CC_ALLGO: 0005604~basement membrane 6 0.00192342 6.56870404 0.02164046GOTERM_MF_ALL GO: 0004930~G-protein coupled receptor activity 130.00026195 3.57735882 0.02172968 GOTERM_BP_ALL GO: 0045597~positiveregulation of cell differentiation 13 0.00125057 3.00345662 0.02397951GOTERM_MF_ALL GO: 0004896~cytokine receptor activity 7 0.000257027.58468866 0.02483432 GOTERM_BP_ALL GO: 0051249~regulation of lymphocyteactivation 10 0.00150309 3.67089142 0.02825331 GOTERM_BP_ALL GO:0007179~transforming growth factor beta receptor signaling 7 0.001495165.50633714 0.0283535 pathway GOTERM_BP_ALL GO: 0043627~response toestrogen stimulus 8 0.00152438 4.63691548 0.02840023 GOTERM_BP_ALL GO:0009888~tissue development 21 0.00154092 2.17491686 0.02845818GOTERM_MF_ALL GO: 0001871~pattern binding 9 0.00041201 4.953266060.02978498 GOTERM_MF_ALL GO: 0030247~polysaccharide binding 9 0.000412014.95326606 0.02978498 GOTERM_BP_ALL GO: 0006869~lipid transport 100.00175493 3.59108944 0.03207509 GOTERM_BP_ALL GO: 0050818~regulation ofcoagulation 5 0.00177021 9.17722856 0.03207792 GOTERM_BP_ALL GO:0032946~positive regulation of mononuclear cell proliferation 60.00184227 6.60760456 0.03308502 GOTERM_BP_ALL GO: 0070665~positiveregulation of leukocyte proliferation 6 0.00184227 6.60760456 0.03308502GOTERM_BP_ALL GO: 0050671~positive regulation of lymphocyteproliferation 6 0.00184227 6.60760456 0.03308502 GOTERM_BP_ALL GO:0002526~acute inflammatory response 7 0.00191336 5.25604908 0.03405697GOTERM_BP_ALL GO: 0043066~negative regulation of apoptosis 18 0.00209122.29607881 0.0365633 GOTERM_BP_ALL GO: 0042592~homeostatic process 250.00207425 1.95260182 0.03656882 GOTERM_BP_ALL GO: 0007204~elevation ofcytosolic calcium ion concentration 7 0.00215298 5.13924799 0.03732145KEGG_PATHWAY hsa04610: Complement and coagulation cascades 6 0.001128127.15463138 0.0376508 GOTERM_BP_ALL GO: 0009617~response to bacterium 100.00219498 3.47768661 0.03773294 GOTERM_BP_ALL GO: 0043069~negativeregulation of programmed cell death 18 0.00237947 2.26978783 0.04051986GOTERM_BP_ALL GO: 0009725~response to hormone stimulus 16 0.002417572.42480901 0.04083361 GOTERM_BP_ALL GO: 0031328~positive regulation ofcellular biosynthetic process 25 0.00244022 1.92979105 0.04088828GOTERM_BP_ALL GO: 0060548~negative regulation of cell death 180.00248193 2.26115745 0.04125275 GOTERM_MF_ALL GO: 0030246~carbohydratebinding 14 0.00073273 3.01503152 0.0421143 GOTERM_CC_ALL GO:0000267~cell fraction 32 0.00404178 1.69344233 0.04306656 GOTERM_MF_ALLGO: 0019899~enzyme binding 25 0.0008491 2.08872665 0.04431816GOTERM_MF_ALL GO: 0001608~nucleotide receptor activity, G-proteincoupled 5 0.00070835 11.5576208 0.04516455 GOTERM_MF_ALL GO:0045028~purinergic nucleotide receptor activity, G-protein coupled 50.00070835 11.5576208 0.04516455 GOTERM_BP_ALL GO: 0050801~ionhomeostasis 15 0.00286437 2.47785171 0.04710319 GOTERM_BP_ALL GO:0003008~system process 26 0.00293122 1.87143484 0.04745392 GOTERM_BP_ALLGO: 0040012~regulation of locomotion 11 0.00291736 3.07981569 0.04759185GOTERM_BP_ALL GO: 0031349~positive regulation of defense response 70.00300863 4.81804499 0.04831554 GOTERM_BP_ALL GO: 0009891~positiveregulation of biosynthetic process 25 0.00310955 1.89438204 0.04916602GOTERM_BP_ALL GO: 0009966~regulation of signal transduction 310.00313297 1.73884331 0.04916714 GOTERM_BP_ALL GO: 0060341~regulation ofcellular localization 11 0.00310259 3.05393488 0.04942072

Among the top probesets downregulated by Copaxone with FC≦1.3, sixpathways were enriched. This includes developmental processes (as alsoseen in prior studies e.g. FDA-2014-P-0933-0001 available atwww.regulations.gov/#!documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein), and cell-cell adhesion related pathways.

The top 25 pathways enriched among top upregulated probesets are shownin Table 25, and FIG. 35 illustrates pathways enriched among topprobesets differentially modulated by Copaxone® (|FC|≧1.3, FDR p<0.05).As an example of an enriched pathway anticipated to be relevant toCopaxone® mechanism of action, cytokine-cytokine receptor interaction,the individual genes modulated by Copaxone® involved in this pathway aredepicted in FIG. 36.

TABLE 25 Top Pathways enriched among top probesets upregulated byCopaxone ® Category Term Count^(a) Adjusted P value GO Cellular GO:0005886~plasma membrane 122 5.85E−23 Compartment GO Cellular GO:0031226~intrinsic to plasma 58 8.04E−17 Compartment membrane GOBiological Process GO: 0009611~response to wounding 44 2.16E−16 GOBiological Process GO: 0009605~response to external 58 2.34E−16 stimulusGO Biological Process GO: 0050896~response to stimulus 118 4.45E−16 GOCellular GO: 0005887~integral to plasma 56 6.29E−16 Compartment membraneGO Biological Process GO: 0006955~immune response 46 4.79E−14 GOBiological Process GO: 0002376~immune system process 59 5.97E−14 GOCellular GO: 0016020~membrane 174 6.33E−13 Compartment GO Cellular GO:0005576~extracellular region 58 6.45E−13 Compartment GO BiologicalProcess GO: 0006952~defense response 40 3.86E−12 GO Cellular GO:0044459~plasma membrane part 76 4.00E−12 Compartment GO MolecularFunction GO: 0004888~transmembrane receptor 39 8.19E−12 activity GOMolecular Function GO: 0060089~molecular transducer 69 1.15E−11 activityGO Molecular Function GO: 0004871~signal transducer activity 69 1.15E−11GO Molecular Function GO: 0004872~receptor activity 56 2.05E−11 GOCellular GO: 0044421~extracellular region part 37 5.16E−11 CompartmentGO Biological Process GO: 0006954~inflammatory response 28 3.57E−10 GOCellular GO: 0031224~intrinsic to membrane 125 3.08E−09 Compartment GOCellular GO: 0016021~integral to membrane 121 8.31E−09 Compartment GOCellular GO: 0044425~membrane part 146 3.43E−08 Compartment Kegg Pathwayhsa04060: Cytokine-cytokine receptor 21 5.00E−08 interaction GO CellularGO: 0005615~extracellular space 27 5.72E−08 Compartment GO BiologicalProcess GO: 0006950~response to stress 70 1.44E−07 GO Biological ProcessGO: 0042060~wound healing 19 1.90E−07 ^(a)Count refers to number ofgenes within the list of interest annotated to the pathway. GO database:Ashburner, M. et al. Gene ontology: tool for the unification of biology.The Gene Ontology Consortium. Nat. Genet. 25, 25-29 (2000). Keggdatabase: Kanehisa, M. & Goto, S. KEGG: kyoto encyclopedia of genes andgenomes. Nucleic Acids Res. 28, 27-30 (2000). Copaxone MoA discussion

The fact that 12,115 probesets are significantly modulated by Copaxonerelative to mannitol provides a window into the complexity ofCopaxone®'s mechanism of action on antigen-presenting cells. Despite thecomplexity and scope of this modulation, key genes known to be modulatedby Copaxone® (such as IL1RN, IL1ORA) appear in the expecteddirectionality. These modulated genes are significantly enriched inimmunology-related pathways which are known to be relevant forCopaxone's mechanism of action. These two aspects combined togethervalidate the design of the study and its ability to identify relevantaspects of a medicine's interaction with antigen-presenting cells.

Polimunol and Copaxone® Comparison: Differentially Expressed Genes

Comparison of Polimunol versus Copaxone® treatment, corrected forMannitol control expression [i.e.(Polimunol-Mannitol)-(Copaxone-Mannitol)], resulted in 807 probesetsdifferentially expressed with FDR-adjusted p<0.05. Upon filtering for“present” calls only, 518 upregulated probesets and 289 downregulatedprobesets were detected.

After conservative filtering out of highly variable probesets (i.e. thefew previously identified to have differing behavior between THP-1studies, which removed 3.5% of the 807 probesets), 779 modulatedprobesets persist: 494 upregulated probesets and 285 downregulatedprobesets. After these filtering steps, the top 25 upregulated probesetsare shown in Table 26, and the top 25 downregulated probesets are shownin Table 27.

TABLE 26 Probesets significantly upregulated in Polimunol versusCopaxone ® Probeset Gene raw.FC P.Value adj.P.Value 212665_at TIPARP1.18 2.68E−17 1.47E−12 202436_s_at CYP1B1 1.41 1.64E−15 4.49E−11224735_at CYBASC3 1.16 3.50E−14 6.37E−10 209921_at SLC7A11 1.35 2.57E−133.51E−09 202435_s_at CYP1B1 1.37 3.31E−13 3.62E−09 208937_s_at ID1 1.221.03E−12 9.43E−09 202434_s_at CYP1B1 1.42 2.03E−12 1.58E−08 228964_atPRDM1 1.24 3.29E−12 2.07E−08 223113_at TMEM138 1.11 3.40E−12 2.07E−08230966_at IL4I1 1.33 1.60E−11 8.74E−08 202014_at PPP1R15A 1.24 1.86E−119.24E−08 202437_s_at CYP1B1 1.34 2.45E−11 1.06E−07 37028_at PPP1R15A1.19 2.52E−11 1.06E−07 39402_at IL1B 1.23 3.09E−11 1.21E−07 205067_atIL1B 1.28 4.02E−11 1.47E−07 217678_at SLC7A11 1.29 6.91E−11 2.36E−07216598_s_at CCL2 1.35 8.57E−11 2.67E−07 203821_at HBEGF 1.24 8.80E−112.67E−07 201468_s_at NQO1 1.16 9.34E−11 2.69E−07 225252_at SRXN1 1.121.12E−10 3.07E−07 211307_s_at FCAR 1.27 1.31E−10 3.41E−07 209928_s_atMSC 1.19 1.40E−10 3.48E−07 201266_at TXNRD1 1.07 2.22E−10 5.28E−07210519_s_at NQO1 1.14 3.76E−10 8.22E−07 212171_x_at VEGF 1.14 1.22E−092.46E−06

TABLE 27 Probesets significantly downregulated in Polimunol versusCopaxone ® Probeset Gene raw.FC P.Value adj.P.Val. 204614_at SERPINB2−1.16 4.60E−10 9.68E−07 211421_s_at RET −1.13 1.75E−09 3.41E−06207725_at POU4F2 −1.16 3.49E−09 6.15E−06 208206_s_at RASGRP2 −1.111.56E−08 1.82E−05 218971_s_at HSPC049 −1.15 3.32E−08 3.04E−05 222799_atHSPC049 −1.17 5.13E−08 4.25E−05 219463_at C20ORF103 −1.11 6.49E−085.22E−05 218858_at DEPDC6 −1.17 8.64E−08 6.72E−05 214539_at SERPINB10−1.14 1.06E−07 7.91E−05 225510_at OAF −1.08 1.88E−07 0.000121086228855_at LOC645919 −1.13 2.00E−07 0.000125905 200799_at HSPA1A −1.092.92E−07 0.000168544 206643_at HAL −1.11 3.17E−07 0.000176999 44790_s_atC13ORF18 −1.11 3.23E−07 0.000178591 202441_at SPFH1 −1.09 5.23E−070.000255211 206034_at SERPINB8 −1.08 7.06E−07 0.000321557 203685_at BCL2−1.16 7.53E−07 0.000340412 216733_s_at GATM −1.09 8.49E−07 0.000374363224428_s_at CDCA7 −1.07 8.91E−07 0.000386704 201310_s_at C5ORF13 −1.111.13E−06 0.000455961 213361_at TDRD7 −1.16 1.28E−06 0.000504959219714_s_at CACNA2D3 −1.09 1.40E−06 0.000542581 35974_at LRMP −1.121.69E−06 0.000628259 201309_x_at C5ORF13 −1.12 1.96E−06 0.000705871243824_at — −1.18 2.13E−06 0.000730854

As observed in the earlier study of the same design(FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein), Polimunol consistently upregulated CYP1B1 relative toCopaxone® (all four probesets on chip: FDR p values 4.5e-11, 3.6e-9,1.6e-8, 1.1e-7, See FIG. 37).

However, ADRB2 was not significantly downregulated by Polimunol relativeto Copaxone® in the second set of studies (FC −1.06, nominal p 0.06).

The probesets significantly differentially expressed between Polimunoland Copaxone® treatment (corrected for mannitol control) in THP-1 cellsis provided in Table 28.

TABLE 28 Probesets significantly differentially expressed betweenPolimunol and Copaxone ® treatment (corrected for mannitol control) inTHP-1 cells. Probeset Gene raw. FC AveExpr t P. Value adj. P. Val B212665_at TIPARP 1.18491814 9.07215527 11.883114 2.68E−17 1.47E−1227.6284062 202436_s_at CYP1B1 1.40629663 10.5046627 10.7394789 1.64E−154.49E−11 23.9781074 224735_at CYBASC3 1.16280829 11.1371084 9.915922523.50E−14 6.37E−10 21.2319004 209921_at SLC7A11 1.34875797 8.019386069.38858221 2.57E−13 3.51E−09 19.4266298 202435_s_at CYP1B1 1.3682447910.7674593 9.32190062 3.31E−13 3.62E−09 19.1959747 208937_s_at ID11.21578992 9.79600279 9.02417027 1.03E−12 9.43E−09 18.1600689202434_s_at CYP1B1 1.42360365 8.59154176 8.84918014 2.03E−12 1.58E−0817.5468656 228964_at PRDM1 1.24239601 8.33311381 8.72349013 3.29E−122.07E−08 17.1045709 223113_at TMEM138 1.1063561 11.1028453 8.714725523.40E−12 2.07E−08 17.0736735 230966_at IL4I1 1.32516688 8.367040388.31508719 1.60E−11 8.74E−08 15.657823 202014_at PPP1R15A 1.236644548.57467088 8.27614067 1.86E−11 9.24E−08 15.5191648 202437_s_at CYP1B11.34228274 11.0857103 8.20543116 2.45E−11 1.06E−07 15.2671479 37028_atPPP1R15A 1.18998338 9.10953004 8.19801576 2.52E−11 1.06E−07 15.240698639402_at IL1B 1.22916144 8.58599227 8.14511174 3.09E−11 1.21E−0715.0518933 205067_at IL1B 1.27678411 8.78154185 8.0777594 4.02E−111.47E−07 14.8112634 217678_at SLC7A11 1.28685305 7.69726333 7.938742646.91E−11 2.36E−07 14.3137409 216598_s_at CCL2 1.34792469 9.285961627.88363055 8.57E−11 2.67E−07 14.116209 203821_at HBEGF 1.235900039.26713046 7.87666898 8.80E−11 2.67E−07 14.0912465 201468_s_at NQO11.15576656 9.35668628 7.86152927 9.34E−11 2.69E−07 14.0369508 225252_atSRXN1 1.11737221 9.70265778 7.81446478 1.12E−10 3.07E−07 13.8680929211307_s_at FCAR 1.27074012 7.1312048 7.77503632 1.31E−10 3.41E−0713.7265534 209928_s_at MSC 1.18769631 8.08116641 7.75739241 1.40E−103.48E−07 13.6631936 201266_at TXNRD1 1.06947321 11.9113637 7.63962932.22E−10 5.28E−07 13.239984 210519_s_at NQO1 1.13794807 10.68168597.50492043 3.76E−10 8.22E−07 12.7552954 212171_x_at VEGF 1.136740519.43661194 7.20421256 1.22E−09 2.46E−06 11.6719358 38037_at HBEGF1.18482724 7.98711019 7.0523034 2.20E−09 4.14E−06 11.1244167 201118_atPGD 1.07758185 12.4845488 6.97857101 2.93E−09 5.34E−06 10.8587242203045_at NINJ1 1.12384597 9.41715175 6.88585707 4.21E−09 7.19E−0610.5247541 216250_s_at LPXN 1.24070246 10.2461732 6.84611362 4.91E−097.90E−06 10.3816492 210512_s_at VEGF 1.17453419 10.5171208 6.846064114.91E−09 7.90E−06 10.3814709 210592_s_at SAT1 1.14616249 9.857112116.78833303 6.15E−09 9.16E−06 10.1736745 210095_s_at IGFBP3 1.261267777.77688369 6.7861051 6.20E−09 9.16E−06 10.1656573 208893_s_at DUSP61.23681965 10.7702231 6.7782857 6.39E−09 9.20E−06 10.1375206 202284_s_atCDKN1A 1.12078798 10.6198443 6.75691033 6.95E−09 9.69E−06 10.0606157209122_at ADFP 1.14098228 12.3228398 6.75171809 7.09E−09 9.69E−0610.0419373 228937_at C13ORF31 1.17921905 8.37907051 6.70099976 8.63E−091.15E−05 9.8595365 201235_s_at BTG2 1.28386355 7.44589095 6.645393271.07E−08 1.39E−05 9.65967492 203927_at NFKBIE 1.12895866 9.726402396.63162768 1.13E−08 1.44E−05 9.61021946 1553141_at C13ORF31 1.190000466.93831195 6.55368898 1.53E−08 1.82E−05 9.33038387 220266_s_at KLF41.1368523 8.46464122 6.55037647 1.55E−08 1.82E−05 9.31849743 217995_atSQRDL 1.0793508 12.336991 6.54729812 1.57E−08 1.82E−05 9.30745172207674_at FCAR 1.24494467 7.73429071 6.53420308 1.65E−08 1.88E−059.26047019 46665_at SEMA4C 1.10637799 10.5657844 6.4481698 2.30E−082.53E−05 8.95205496 210264_at GPR35 1.11391738 8.72115064 6.446280032.32E−08 2.53E−05 8.94528559 211668_s_at PLAU 1.11120293 9.23536546.42233001 2.54E−08 2.69E−05 8.85951421 205205_at RELB 1.164927067.34250559 6.42094346 2.56E−08 2.69E−05 8.85454977 203798_s_at VSNL11.16614475 7.2833092 6.41517707 2.61E−08 2.70E−05 8.83390503 219634_atCHST11 1.11031386 9.57653235 6.40091795 2.76E−08 2.75E−05 8.78286459201502_s_at NFKBIA 1.14603586 11.2391775 6.40005102 2.77E−08 2.75E−058.77976186 229055_at GPR68 1.14767352 7.68909756 6.36111525 3.22E−083.04E−05 8.64046681 212190_at SERPINE2 1.12333317 9.662056 6.35197223.34E−08 3.04E−05 8.60777296 219386_s_at SLAMF8 1.34835612 8.408906126.31827296 3.80E−08 3.41E−05 8.48732535 210513_s_at VEGF 1.151912858.36243556 6.28246816 4.36E−08 3.85E−05 8.35944956 211527_x_at VEGF1.13731715 7.87125822 6.26106285 4.74E−08 4.11E−05 8.283051061555638_a_a SAMSN1 1.16504788 8.69549173 6.24146956 5.11E−08 4.25E−058.21315379 204470_at CXCL1 1.35501196 7.67502936 6.24129687 5.11E−084.25E−05 8.2125379 220935_s_at CDK5RAP2 1.10875555 9.47138345 6.119022248.18E−08 6.48E−05 7.7771196 201236_s_at BTG2 1.39106574 9.518198346.10195957 8.73E−08 6.72E−05 7.71647403 228648_at LRG1 1.1366765710.1778893 6.09346129 9.02E−08 6.85E−05 7.68627977 212143_s_at IGFBP31.19756801 7.50292055 6.0375024 1.12E−07 8.26E−05 7.48764791 240076_at —1.11560154 7.77294938 6.02250815 1.18E−07 8.63E−05 7.43448169215223_s_at SOD2 1.08832613 9.38708957 6.00345187 1.27E−07 9.16E−057.36694855 208891_at DUSP6 1.20973898 11.4952332 5.99682168 1.31E−079.18E−05 7.34346158 228967_at EIF1 1.09256705 7.51282579 5.994302191.32E−07 9.18E−05 7.33453779 201489_at PPIF 1.07056711 11.97452235.98944612 1.34E−07 9.18E−05 7.31734011 202388_at RGS2 1.267736649.57646356 5.97863153 1.40E−07 9.45E−05 7.27905017 221903_s_at CYLD1.09642353 9.26863731 5.97193254 1.44E−07 9.58E−05 7.25533872 1560228_atSNAI3 1.15060555 7.09991102 5.93825721 1.63E−07 0.0001076 7.13622321227034_at ANKRD57 1.22029842 7.32299473 5.88467981 2.00E−07 0.00012596.94699581 200878_at EPAS1 1.12190973 8.895976 5.87823307 2.05E−070.00012757 6.9242512 201005_at CD9 1.14821208 9.10086802 5.869835842.12E−07 0.00013023 6.89463315 206026_s_at TNFAIP6 1.19240437 5.363727035.85839211 2.21E−07 0.00013373 6.85428439 214290_s_at HIST2H2AA /1.09794003 11.8199009 5.85526922 2.24E−07 0.00013373 6.84327656222670_s_at MAFB 1.20369944 9.73888237 5.854147 2.25E−07 0.000133736.83932116 205153_s_at CD40 1.13334093 8.72577521 5.82226469 2.54E−070.00014934 6.72701829 225390_s_at KLF13 1.08054083 10.877664 5.784798542.93E−07 0.00016854 6.59522285 227080_at ZNF697 1.12343463 8.920127525.76864695 3.11E−07 0.000177 6.5384663 214056_at MCL1 1.091481428.9472801 5.76468003 3.16E−07 0.000177 6.52453225 201739_at SGK1.28779242 8.00577284 5.75044243 3.34E−07 0.00018189 6.47454023201170_s_at BHLHB2 1.09531573 9.50744497 5.74853964 3.36E−07 0.000181896.46786122 205633_s_at ALAS1 1.08179152 11.5068057 5.74324623 3.43E−070.00018376 6.44928355 203665_at HMOX1 1.24623576 9.15770135 5.72894933.62E−07 0.00019209 6.39912762 203936_s_at MMP9 1.145748 8.561154555.70212398 4.01E−07 0.0002066 6.30510148 213988_s_at SAT1 1.129935489.10818688 5.68515244 4.27E−07 0.00021822 6.24566986 225097_at HIPK21.16355832 9.37790876 5.66703291 4.57E−07 0.00023152 6.18226665226218_at — 1.2939063 6.28386762 5.66047476 4.69E−07 0.000235146.15933112 203939_at NT5E 1.19431475 7.2701384 5.6470707 4.93E−070.00024509 6.11247457 221840_at PTPRE 1.10358333 8.99406461 5.640333125.06E−07 0.00024914 6.0889327 234994_at KIAA1913 1.26172422 6.191655695.61287248 5.61E−07 0.00026903 5.99305687 201169_s_at BHLHB2 1.11383487.81678741 5.60701185 5.73E−07 0.00027264 5.97261084 223222_at SLC25A191.06195494 11.1387437 5.60415209 5.80E−07 0.00027322 5.96263602201250_s_at SLC2A1 1.07198576 9.45224146 5.58245393 6.29E−07 0.000292875.88699657 205770_at GSR 1.08507865 10.4221632 5.58115446 6.32E−070.00029287 5.88246909 211610_at KLF6 1.21373848 7.58295098 5.569732886.60E−07 0.00030315 5.84268743 217996_at PHLDA1 1.33234556 7.226448615.52201205 7.89E−07 0.00035373 5.6767135 204440_at CD83 1.095599159.65465598 5.51721887 8.04E−07 0.00035722 5.66006438 203751_x_at JUND1.11709364 8.15242666 5.49344944 8.78E−07 0.00038425 5.57756091220330_s_at SAMSN1 1.16271877 9.59945919 5.48604123 9.03E−07 0.000388845.55186756 202644_s_at TNFAIP3 1.10355352 10.1094931 5.47992259 9.24E−070.00039474 5.53065412 203797_at VSNL1 1.10477681 8.15296158 5.477016859.34E−07 0.00039597 5.52058224 201069_at MMP2 1.10375779 8.406971765.45565127 1.01E−06 0.00042561 5.44657164 204653_at TFAP2A 1.171429327.72005745 5.44704422 1.05E−06 0.00043617 5.41678026 219385_at SLAMF81.21995297 7.92135191 5.44342079 1.06E−06 0.00043648 5.40424263208926_at NEU1 1.08099136 10.7507527 5.44280336 1.06E−06 0.000436485.40210647 239412_at IRF5 1.07460841 10.9779751 5.42713112 1.13E−060.00045596 5.34790799 223501_at — 1.1103323 9.76378918 5.425135741.13E−06 0.00045596 5.34101078 201651_s_at PACSIN2 1.05371079 12.46896975.41770064 1.17E−06 0.00046511 5.31531719 214211_at FTH1 1.1528311110.7669406 5.41590299 1.17E−06 0.00046511 5.30910659 202988_s_at RGS11.26703574 6.64018217 5.37761912 1.35E−06 0.00052878 5.17698759223303_at URP2 1.07136267 11.4584296 5.36688864 1.41E−06 0.000542585.14000695 36711_at MAFF 1.19353834 6.77574709 5.36039903 1.44E−060.00055196 5.11765264 203508_at TNFRSF1B 1.11118203 9.418007255.35852346 1.45E−06 0.00055196 5.1111935 227645_at PIK3R5 1.104368838.17453287 5.33951385 1.56E−06 0.0005883 5.04576711 218501_at ARHGEF31.11215762 8.30700755 5.31477003 1.71E−06 0.00063184 4.96071299209606_at PSCDBP 1.18667973 7.12974957 5.30711238 1.76E−06 0.000645694.93441572 1555756_a_a CLEC7A 1.21395231 6.44819327 5.2975806 1.82E−060.00066446 4.90169919 229354_at PDCD6 /// A

1.08957565 10.3878046 5.29027036 1.87E−06 0.00067819 4.87662042233955_x_at CXXC5 1.07971504 12.6052495 5.27206493 2.00E−06 0.000712774.81421221 203887_s_at THBD 1.14864911 11.9807825 5.27153474 2.01E−060.00071277 4.81239575 233540_s_at CDK5RAP2 1.08483341 10.22270115.26920484 2.03E−06 0.00071431 4.80441408 209774_x_at CXCL2 1.337970356.42227624 5.26653762 2.05E−06 0.00071677 4.79527824 210845_s_at PLAUR1.12269107 10.7660847 5.26173913 2.08E−06 0.0007209 4.77884607 225980_atC14ORF43 1.0793459 9.21104798 5.23040107 2.34E−06 0.00079874 4.67165036219039_at SEMA4C 1.11139871 9.52722178 5.2215591 2.41E−06 0.00081544.64144331 228754_at SLC6A6 1.11066199 9.56424888 5.21977863 2.43E−060.0008154 4.63536267 222062_at IL27RA 1.14734393 8.84896859 5.216004922.47E−06 0.0008189 4.62247702 208892_s_at DUSP6 1.19436158 11.08414365.21531302 2.47E−06 0.0008189 4.62011481 204684_at NPTX1 1.285330889.73612701 5.20831506 2.54E−06 0.00083526 4.59622895 208373_s_at P2RY61.06697743 9.65819159 5.20192905 2.60E−06 0.00084937 4.57444113218856_at TNFRSF21 1.11783326 11.1389024 5.20052327 2.61E−06 0.000849374.56964607 204436_at PLEKHQ1 1.09698664 9.3889143 5.19357309 2.68E−060.0008652 4.54594574 212227_x_at EIF1 1.05443994 12.7811739 5.192305342.69E−06 0.0008652 4.54162382 223125_s_at C1ORF21 1.11079328 10.49374935.18218325 2.79E−06 0.00089281 4.50712903 217997_at PHLDA1 1.267445716.13655327 5.17537259 2.86E−06 0.0009049 4.48393197 204912_at IL10RA1.12420434 9.40611087 5.17279988 2.89E−06 0.00090826 4.47517201218417_s_at FLJ20489 1.08815767 9.3505492 5.15361341 3.10E−06 0.00095144.4098898 203888_at THBD 1.15159161 10.9696824 5.15288486 3.11E−060.0009514 4.40741251 205419_at EBI2 1.18215692 9.40684523 5.15275133.11E−06 0.0009514 4.4069584 228708_at RAB27B 1.18815027 7.906849355.15257387 3.11E−06 0.0009514 4.40635511 200644_at MARCKSL1 1.1069045211.028723 5.15248432 3.11E−06 0.0009514 4.40605064 202021_x_at EIF11.05923104 12.6600822 5.1394264 3.27E−06 0.00099262 4.36167177211653_x_at AKR1C2 1.12714868 8.13501584 5.12100436 3.50E−06 0.001047534.29912857 209882_at RIT1 1.10219332 10.0435725 5.12025544 3.51E−060.00104753 4.29658764 201467_s_at NQO1 1.11423301 9.57842418 5.106805823.68E−06 0.00109451 4.25097768 225842_at PHLDA1 1.16531676 7.085795625.09284521 3.88E−06 0.00114573 4.20367946 220091_at SLC2A6 1.116566369.02115478 5.08631413 3.97E−06 0.00116392 4.18156801 200920_s_at BTG11.06979743 10.8993308 5.08304104 4.02E−06 0.00116392 4.17049051222703_s_at YRDC 1.06438343 10.3475422 5.08288187 4.02E−06 0.001163924.1699519 201490_s_at PPIF 1.05947022 11.5950549 5.07132874 4.19E−060.00120065 4.13087206 218223_s_at PLEKHO1 1.12093336 9.105755825.06452081 4.30E−06 0.00122451 4.10785829 201851_at SH3GL1 1.079018729.65074195 5.02668705 4.94E−06 0.00138427 3.98016723 228124_at ABHD121.09977731 7.66951417 5.01836495 5.09E−06 0.00141465 3.95212649218559_s_at MAFB 1.22135659 10.2200187 5.01793255 5.10E−06 0.001414653.95066998 228696_at SLC45A3 1.12825933 7.72464342 5.01306718 5.19E−060.00143268 3.93428488 223660_at ADORA3 1.13136045 7.77795316 4.985863525.73E−06 0.00155048 3.84277934 220066_at CARD15 1.12730802 7.88102794.98180156 5.81E−06 0.0015658 3.82913191 238542_at ULBP2 1.105899617.94992924 4.9769201 5.92E−06 0.00158601 3.81273664 224480_s_atLPAAT-THET

1.20881651 8.02630766 4.96873318 6.10E−06 0.00162593 3.78525289207469_s_at PIR 1.10472357 9.02435046 4.96686989 6.14E−06 0.001629023.77900012 202241_at TRIB1 1.67898747 9.30574701 4.94914352 6.55E−060.00172797 3.71955903 204975_at EMP2 1.07979325 8.71044082 4.941025976.74E−06 0.00176349 3.69236569 226354_at LACTB 1.06792187 9.98288764.93326158 6.93E−06 0.00179962 3.66637136 226022_at SASH1 1.0796024311.2682799 4.93280332 6.95E−06 0.00179962 3.66483764 228869_at SLIC11.07164715 9.82112889 4.92528486 7.14E−06 0.00184057 3.63968244203752_s_at JUND 1.08201127 11.8110521 4.92340249 7.19E−06 0.001844463.63338672 212130_x_at EIF1 1.05588847 12.6471904 4.91712987 7.35E−060.00187608 3.6124142 219593_at SLC15A3 1.08615216 8.63335571 4.914167697.43E−06 0.00187608 3.60251376 236570_at ZNF366 1.23552697 5.630152674.91397465 7.43E−06 0.00187608 3.60186863 213236_at SASH1 1.0988124310.3511094 4.91356632 7.45E−06 0.00187608 3.60050408 225609_at GSR1.08973861 9.95822522 4.90544456 7.67E−06 0.00192315 3.57337186205891_at ADORA2B 1.11169386 9.89367673 4.87112294 8.68E−06 0.002162823.45890752 228438_at TRPA1 1.12226677 8.86862388 4.87039478 8.70E−060.00216282 3.45648245 226372_at CHST11 1.08446345 11.0281604 4.86866048.76E−06 0.00216654 3.45070693 204961_s_at NCF1 /// LO

1.09199637 10.3669364 4.86594187 8.84E−06 0.00217803 3.44165575212124_at RAI17 1.09160138 9.61628437 4.84935418 9.39E−06 0.002301823.38647153 204341_at TRIM16 /// T

1.10230923 8.04807245 4.83779913 9.79E−06 0.0023573 3.34807425233857_s_at ASB2 1.10322519 6.77376513 4.82807168 1.01E−05 0.002430533.31577846 205479_s_at PLAU 1.08239048 9.99849286 4.82413541 1.03E−050.00244373 3.30271717 202252_at RAB13 1.04918345 12.5262785 4.814954191.06E−05 0.00251476 3.27226887 204363_at F3 1.13756401 8.528173864.80950401 1.08E−05 0.00254245 3.25420514 226389_s_at RAPGEF1 1.0944936910.0900401 4.80799583 1.09E−05 0.00254533 3.24920801 238893_at LOC3387581.19879171 8.45854652 4.79847311 1.13E−05 0.00260733 3.217670441559399_s_at ZCCHC10 1.08397924 9.324417 4.79836233 1.13E−05 0.002607333.21730369 213281_at JUN 1.32929059 8.21180845 4.79539679 1.14E−050.00260733 3.20748765 35150_at CD40 1.0785382 10.2548276 4.78107061.20E−05 0.00272195 3.16010228 237252_at THBD 1.17836626 8.939812424.7780675 1.21E−05 0.00274002 3.15017657 204908_s_at BCL3 1.150861387.37503762 4.76630513 1.26E−05 0.00282288 3.11132484 200884_at CKB1.07535296 9.92747723 4.76403187 1.28E−05 0.00282288 3.10382067222996_s_at CXXC5 1.07526087 11.470336 4.76122287 1.29E−05 0.00283993.09455008 209949_at NCF2 1.0957522 12.1194106 4.75475484 1.32E−050.00289468 3.07321208 214175_x_at PDLIM4 1.10938746 10.06541944.75115423 1.34E−05 0.00292045 3.06133891 211924_s_at PLAUR 1.111655119.95057637 4.74398245 1.37E−05 0.00298199 3.0377008 208786_s_at MAP1LC3B1.06211193 10.0695592 4.71562836 1.52E−05 0.00321787 2.94439234211005_at LAT 1.08938993 7.96306748 4.71210161 1.54E−05 0.003240532.93280287 205681_at BCL2A1 1.21178632 7.93446379 4.70888129 1.55E−050.00326531 2.92222355 239529_at C5ORF20 1.07787194 9.92848977 4.706514141.57E−05 0.00328034 2.91444905 211564_s_at PDLIM4 1.14599993 9.56255894.69674734 1.62E−05 0.00338345 2.88238905 216834_at RGS1 1.239773018.08711615 4.69312858 1.64E−05 0.00341426 2.87051745 205468_s_at IRF51.07554402 9.22742578 4.6798859 1.72E−05 0.00356532 2.82710733201465_s_at JUN 1.4322588 8.69995542 4.64844489 1.92E−05 0.003912122.72425354 204059_s_at ME1 1.12987509 10.6613264 4.64336736 1.96E−050.0039684 2.70767146 219926_at POPDC3 1.14627403 7.07974513 4.629898682.06E−05 0.00414687 2.66372393 203217_s_at ST3GAL5 1.09010335 8.642990264.61328701 2.18E−05 0.00431813 2.60959806 203140_at BCL6 1.093701269.09728992 4.60731699 2.23E−05 0.00435798 2.59016685 223394_at SERTAD11.09520636 8.8545176 4.60661454 2.23E−05 0.00435798 2.587881251555832_s_at KLF6 1.3281372 9.3646245 4.60196013 2.27E−05 0.004398772.57274081 202181_at KIAA0247 1.06968044 10.7870044 4.59786925 2.30E−050.00444699 2.55943906 215346_at CD40 1.11448836 7.24866952 4.588435422.38E−05 0.00458129 2.52878443 1554036_at ZBTB24 1.18706647 7.294105954.57607014 2.49E−05 0.00473788 2.48864674 227345_at TNFRSF10D 1.116768777.04849796 4.57591796 2.49E−05 0.00473788 2.48815304 238638_at SLC37A21.13101655 8.61062051 4.57336536 2.51E−05 0.00474087 2.47987348221841_s_at KLF4 1.10113355 10.8767227 4.57011234 2.54E−05 0.004747592.469325 219256_s_at SH3TC1 1.11536627 7.53451496 4.56946119 2.54E−050.00474759 2.46721395 1555950_a_a CD55 1.09152724 10.0342225 4.564891962.59E−05 0.00479572 2.45240406 204702_s_at NFE2L3 1.12411725 7.173279174.56338707 2.60E−05 0.00479572 2.44752785 227811_at FGD3 1.0662947210.1971288 4.56331445 2.60E−05 0.00479572 2.44729254 205505_at GCNT11.07750113 9.23709484 4.55594632 2.67E−05 0.00487889 2.42342858224397_s_at TMTC1 /// L

1.0620857 9.26567514 4.550558 2.72E−05 0.0049228 2.40598784 201642_atIFNGR2 1.05959086 11.6162722 4.54471501 2.78E−05 0.00499333 2.38708599206508_at TNFSF7 1.05574374 11.4883906 4.54463083 2.78E−05 0.004993332.38681375 208091_s_at ECOP 1.04916375 11.1694214 4.54122019 2.81E−050.00502048 2.37578563 200797_s_at MCL1 1.07430577 12.8237735 4.537334762.85E−05 0.00507286 2.36322689 224516_s_at CXXC5 1.06346079 12.18149314.5350953 2.87E−05 0.0050963 2.35599058 202838_at FUCA1 1.080159058.59058103 4.52575753 2.97E−05 0.00521504 2.32586748 218902_at NOTCH11.07544712 10.0281701 4.51751651 3.05E−05 0.00535088 2.299245251556314_a_a — 1.19283635 8.47221892 4.51444845 3.09E−05 0.005391442.2893517 212552_at HPCAL1 1.05856719 11.9497308 4.51088571 3.13E−050.00541251 2.27786684 220307_at CD244 1.06735723 10.3372156 4.500546683.24E−05 0.00557134 2.24456149 1555827_at CCNL1 1.31890926 6.175046094.49891525 3.26E−05 0.00558567 2.23930934 205349_at GNA15 1.068571748.74643664 4.49799127 3.27E−05 0.00558624 2.23633511 210785_s_at C1ORF381.10692612 9.80722622 4.4919076 3.34E−05 0.00568834 2.21675923209568_s_at RGL1 1.09184408 7.96502675 4.49062407 3.35E−05 0.005688342.21263071 212298_at NRP1 1.20491357 7.7598722 4.49014314 3.36E−050.00568834 2.21108391 223145_s_at C6ORF166 1.05608761 11.48847144.48713202 3.40E−05 0.00573078 2.20140111 204257_at FADS3 1.094939458.41951964 4.48151372 3.46E−05 0.0058264 2.18334247 202686_s_at AXL1.09254285 8.17667586 4.47347755 3.56E−05 0.0059656 2.15753052216080_s_at FADS3 1.09835074 8.00176994 4.46781128 3.63E−05 0.006019252.13934359 223392_s_at TSHZ3 1.06527254 7.90879098 4.46593878 3.66E−050.00604039 2.13333582 55093_at CSGLCA-T 1.06274155 9.78511615 4.46157163.71E−05 0.00611247 2.11964927 234351_x_at TRPS1 1.08022797 8.012373774.45917263 3.74E−05 0.00612832 2.11163694 212882_at KLHL18 1.053779349.17946015 4.45890277 3.75E−05 0.00612832 2.11077186 230698_at —1.13801592 5.25817407 4.45834849 3.75E−05 0.00612832 2.108995011553142_at C13ORF31 1.22937031 5.40269403 4.45539446 3.79E−05 0.00617332.09952717 215195_at PRKCA 1.07061108 8.15580417 4.4501435 3.86E−050.0062686 2.08270483 223305_at MGC13379 1.04781874 10.291887 4.447083073.91E−05 0.00631099 2.07290452 212681_at EPB41L3 1.16483629 6.501953794.44605331 3.92E−05 0.00631099 2.06960767 212225_at EIF1 1.299780258.27092573 4.42703387 4.19E−05 0.00665515 2.00878036 235299_at —1.16674528 5.45895742 4.42210056 4.26E−05 0.00675057 1.993023221658_s_at IL21R 1.1069911 6.7874754 4.41756867 4.33E−05 0.006818131.97855514 223276_at MST150 1.04156368 11.4183626 4.40792637 4.47E−050.00696979 1.9477961 218280_x_at HIST2H2AA /

1.08743247 10.2812164 4.40125238 4.58E−05 0.00711271 1.92652478218647_s_at YRDC 1.06300514 9.78941527 4.38080776 4.92E−05 0.007527631.86146015 218589_at P2RY5 1.1167465 8.63436917 4.37437741 5.03E−050.00764929 1.84102585 207535_s_at NFKB2 1.10079929 6.90974535 4.372950255.05E−05 0.00764929 1.8364926 230925_at APBB1IP 1.06629311 12.05750874.35935406 5.29E−05 0.00795107 1.79334155 48106_at FLJ20489 1.06370339.15515486 4.35698216 5.34E−05 0.00799448 1.78582038 210872_x_at GAS71.08154753 7.70819207 4.35585799 5.36E−05 0.00800363 1.78225642204359_at FLRT2 1.14647669 7.31270266 4.35162998 5.44E−05 0.008065091.76885628 235457_at MAML2 1.11934624 7.88052648 4.35157862 5.44E−050.00806509 1.76869354 209239_at NFKB1 1.06667957 9.95829149 4.349709495.47E−05 0.00808685 1.76277161 57163_at ELOVL1 1.03977111 11.29719964.34572593 5.55E−05 0.00815484 1.75015477 218145_at TRIB3 1.0593826111.0204954 4.33624331 5.73E−05 0.00835029 1.7201439 211776_s_at EPB41L31.13532577 6.97220625 4.3357415 5.74E−05 0.00835029 1.71855664203455_s_at SAT1 1.1106924 10.2329144 4.32750295 5.91E−05 0.008439131.69251066 207571_x_at C1ORF38 1.09650304 9.82311518 4.32655202 5.93E−050.00843913 1.68950588 211661_x_at PTAFR 1.09097156 8.56515505 4.322833396.00E−05 0.00852559 1.67775875 201590_x_at ANXA2 1.0821024 12.51513454.29910185 6.51E−05 0.00910791 1.60290884 202071_at SDC4 1.103463829.40347252 4.29057952 6.71E−05 0.00933036 1.57607916 208983_s_at PECAM11.05734731 11.7319933 4.28529786 6.83E−05 0.00945271 1.55946497205098_at CCR1 1.06303521 11.4600607 4.28157126 6.92E−05 0.009525941.54774856 200839_s_at CTSB 1.0495602 12.4472914 4.27935833 6.97E−050.00952643 1.54079356 205503_at PTPN14 1.11449101 5.88707054 4.271562437.16E−05 0.00973541 1.51630622 204998_s_at ATF5 1.09981149 9.304805934.26739042 7.26E−05 0.00985086 1.50321093 208961_s_at KLF6 1.239371128.76862028 4.26084325 7.43E−05 0.00997486 1.48267336 211962_s_at ZFP36L11.14336043 7.45775693 4.25626247 7.54E−05 0.01008195 1.46831355223502_s_at TNFSF13B 1.09556837 9.8619397 4.25432078 7.59E−05 0.010081951.46222911 212062_at ATP9A 1.12049998 7.42652014 4.24093141 7.95E−050.01044325 1.42031066 222165_x_at C9ORF16 1.06651407 9.917967524.24002979 7.97E−05 0.01044325 1.41749035 201926_s_at CD55 1.092412079.80032696 4.23706219 8.05E−05 0.01046218 1.40820968 214446_at ELL21.08240974 7.5600877 4.23640074 8.07E−05 0.01046218 1.40614158 205718_atITGB7 1.06295759 9.27615896 4.23403904 8.14E−05 0.01049314 1.39875869216504_s_at SLC39A8 1.10938409 7.59501292 4.23284649 8.17E−05 0.010493141.3950315 221799_at CSGLCA-T 1.07612526 9.24334654 4.23263401 8.18E−050.01049314 1.39436746 1554406_a_a CLEC7A 1.10481365 7.940572064.23125877 8.21E−05 0.01051774 1.39007005 41644_at SASH1 1.0763574210.9010644 4.22769131 8.31E−05 0.01058985 1.3789256 238669_at PTGS11.10119423 8.07043819 4.21299805 8.74E−05 0.01101178 1.33307571211571_s_at CSPG2 1.11087565 8.5143978 4.21117973 8.80E−05 0.011054611.32740739 203702_s_at TTLL4 1.05712621 8.43342998 4.2038303 9.02E−050.01130824 1.30450953 209906_at C3AR1 1.12163622 7.99304364 4.191746289.40E−05 0.01159647 1.26690537 221752_at SSH1 1.06296062 8.55650144.18795524 9.52E−05 0.011693 1.25511957 204655_at CCL5 1.0806791311.8965338 4.18339572 9.67E−05 0.01179566 1.24095201 1555788_a_a TRIB31.07151286 9.51438422 4.18231045 9.70E−05 0.01181277 1.23758099209160_at AKR1C3 1.14905554 5.73155063 4.17829766 9.83E−05 0.01187111.22512056 224783_at FAM100B 1.05774261 9.77579353 4.17654931 9.89E−050.0118964 1.21969356 203549_s_at LPL 1.05114008 12.062737 4.176311139.90E−05 0.0118964 1.21895431 230343_at — 1.0958987 7.395281174.17213744 0.00010041 0.01203929 1.20600404 201925_s_at CD55 1.129154659.47556264 4.16888144 0.00010152 0.01212964 1.19590588 214581_x_atTNFRSF21 1.11185517 9.56118012 4.16612537 0.00010247 0.012206491.18736144 215813_s_at PTGS1 1.06554211 10.1951822 4.16354389 0.000103370.0122868 1.17936091 39582_at CYLD 1.07942531 7.63563499 4.162129480.00010387 0.01231894 1.17497847 219890_at CLEC5A 1.14451027 8.863856584.15970971 0.00010472 0.01239328 1.16748282 224218_s_at TRPS1 1.108735937.212934 4.15691737 0.00010572 0.01243643 1.15883589 207275_s_at ACSL11.06382835 10.2365501 4.15687886 0.00010573 0.01243643 1.158716631560485_at HIVEP1 1.09963892 6.29901302 4.14268989 0.00011092 0.012821441.11482542 224967_at UGCG 1.07551513 9.81750879 4.13803967 0.000112670.01294212 1.1004579 235479_at CPEB2 1.05886438 8.76040386 4.133345610.00011447 0.01305473 1.08596354 205323_s_at MTF1 1.05603723 9.759497474.13204585 0.00011497 0.01305473 1.08195167 202643_s_at TNFAIP31.09192276 8.84841512 4.13157653 0.00011516 0.01305473 1.0805032202948_at IL1R1 1.11651018 6.61849267 4.13003859 0.00011575 0.013054731.07575731 205469_s_at IRF5 1.05102073 11.1050752 4.12871511 0.000116270.01305473 1.07167395 211676_s_at IFNGR1 1.05547086 11.597122 4.118802460.00012022 0.01335977 1.04111224 226039_at MGAT4A 1.06778678 10.40270194.10156128 0.0001274 0.01404306 0.98804884 213763_at HIPK2 1.101056497.77301596 4.09563418 0.00012996 0.01425665 0.96983433 222877_at NRP21.15705726 5.02483818 4.09527073 0.00013012 0.01425665 0.96871786228186_s_at RSPO3 1.14318575 5.7292516 4.09151825 0.00013176 0.014379710.95719398 228640_at — 1.18540594 4.77536947 4.08751237 0.000133550.01454523 0.94489812 1558404_at LOC644242 /

1.23417115 5.05041215 4.08679741 0.00013387 0.01455116 0.942704271554966_a_a DOC1 1.09595173 8.58722147 4.0855338 0.00013444 0.014565310.93882738 209803_s_at PHLDA2 1.09168215 8.97143045 4.084883930.00013473 0.01456531 0.93683375 1555759_a_a CCL5 1.08590053 12.36655014.08473429 0.0001348 0.01456531 0.93637472 205322_s_at MTF1 1.061166979.07418068 4.07720028 0.00013824 0.01490832 0.91327536 204197_s_at RUNX31.07101524 9.2606011 4.075793 0.0001389 0.01494692 0.90896318 224785_atFAM100B 1.06028293 9.68830224 4.07291553 0.00014024 0.014946920.90014852 204011_at SPRY2 1.07921096 9.36460861 4.06326541 0.000144850.01535236 0.87061139 218673_s_at ATG7 1.0429976 10.1275004 4.0631760.00014489 0.01535236 0.87033789 244434_at — 1.20479383 5.199080754.05858303 0.00014713 0.01555469 0.85629319 203313_s_at TGIF 1.077920239.34545441 4.05661779 0.0001481 0.01555469 0.85028636 214057_at MCL11.08299074 8.45324848 4.05637551 0.00014822 0.01555469 0.84954593201473_at JUNB 1.18429728 8.79340992 4.05365798 0.00014957 0.015643760.84124255 203234_at UPP1 1.11194547 9.00007417 4.05220054 0.00015030.01565768 0.83679059 223126_s_at C1ORF21 1.0962014 8.746413244.05101842 0.0001509 0.01565768 0.83318028 203604_at ZNF516 1.067611489.49503774 4.05097313 0.00015092 0.01565768 0.83304199 219398_at CIDEC1.06603998 7.6766591 4.05011563 0.00015135 0.01567285 0.83042347241418_at — 1.11426423 6.19780118 4.04745294 0.00015271 0.015782930.82229445 239845_at — 1.14637752 5.55035202 4.04641564 0.000153240.01580779 0.81912842 214010_s_at ATP9B 1.05604217 8.49566348 4.041629490.0001557 0.01601409 0.80452591 201063_at RCN1 1.05280589 9.822353384.02360178 0.00016534 0.01680334 0.74960812 226064_s_at DGAT2 1.052586119.74527668 4.00179079 0.00017778 0.01786795 0.68334514 212419_atC10ORF56 1.07773109 8.71242101 3.99856112 0.0001797 0.017994410.67355005 201199_s_at PSMD1 1.03812334 11.768617 3.99425825 0.000182280.01820614 0.66050691 1554691_a_a PACSIN2 1.05020015 10.52556253.98851731 0.00018579 0.01843526 0.64311668 213503_x_at ANXA2 1.0780240712.4262407 3.98512527 0.00018789 0.01856568 0.63284816 225386_s_atHNRPLL 1.04770359 11.2270978 3.98475235 0.00018812 0.01856568 0.63171954219093_at FLJ20701 1.14335282 6.49529551 3.98380226 0.000188710.01858124 0.62884438 212657_s_at IL1RN 1.06064344 10.3261013 3.978498860.00019206 0.01881842 0.61280238 215411_s_at TRAF3IP2 1.047461319.60905229 3.97606781 0.00019361 0.01893656 0.60545275 224828_at CPEB41.11148606 6.94793798 3.97135657 0.00019665 0.01908993 0.59121672208309_s_at MALT1 1.07563121 7.84016779 3.95900453 0.00020485 0.019753150.55393702 211219_s_at LHX2 1.07519303 8.41763861 3.95580414 0.000207020.01992792 0.54428847 208619_at DDB1 1.04094564 10.905059 3.94937170.00021147 0.02022705 0.52490916 212659_s_at IL1RN 1.06314743 8.369395463.94913045 0.00021164 0.02022705 0.52418269 204401_at KCNN4 1.081966410.2570594 3.94621319 0.00021368 0.02031839 0.51539986 203922_s_at CYBB1.09189933 9.03066782 3.94421507 0.00021509 0.02041722 0.50938632225955_at METRNL ///

1.12640184 9.30736877 3.94080195 0.00021753 0.02054128 0.49911817223019_at C9ORF88 1.11519595 8.77056793 3.93913081 0.00021873 0.020619120.49409247 225372_at C10ORF54 1.11079316 7.82555013 3.936187760.00022086 0.02074849 0.48524461 225368_at HIPK2 1.10811883 10.94361093.93081197 0.00022481 0.02104628 0.46909267 227265_at KIAA15051.17158338 9.78973377 3.92552212 0.00022875 0.02130693 0.45321112238604_at ECOP 1.07570947 9.50546921 3.92153082 0.00023178 0.021515180.44123614 206171_at ADORA3 1.12468497 8.70914475 3.92097723 0.00023220.02151785 0.43957576 200748_s_at FTH1 1.09484808 13.0211632 3.919789820.00023311 0.02156547 0.43601482 204858_s_at ECGF1 1.07328226 10.09941323.91907356 0.00023366 0.0215798 0.43386711 226534_at KITLG 1.073302969.3627121 3.90512624 0.00024461 0.02229014 0.3920904 225407_at MBP1.05793961 11.3278556 3.90258448 0.00024666 0.02243941 0.38448614216594_x_at AKR1C1 1.08731511 8.97660025 3.90054274 0.000248320.02255267 0.37837983 242157_at — 1.10450816 7.85915836 3.899007550.00024957 0.02262757 0.37378967 203104_at CSF1R 1.066843 11.25587383.89852024 0.00024997 0.02262757 0.37233286 201471_s_at SQSTM11.06817603 11.064824 3.8911549 0.00025608 0.02302792 0.35032669201565_s_at ID2 1.05840108 12.351258 3.88999177 0.00025705 0.023068930.34685365 201412_at LRP10 1.0522513 10.0558306 3.8879203 0.00025880.0231589 0.34066984 208982_at PECAM1 1.04940273 12.4408294 3.885795210.00026061 0.02324451 0.33432794 242302_at APRIN 1.09399636 6.083668623.88405566 0.0002621 0.02333917 0.32913805 201920_at SLC20A1 1.050538811.1251381 3.87844015 0.00026696 0.02365634 0.31239348 214084_x_atLOC648998 /

1.07297813 9.87462439 3.87717059 0.00026807 0.02367801 0.30860978202804_at ABCC1 1.05325862 10.0332207 3.86552597 0.00027847 0.024399240.27393816 228532_at C1ORF162 1.06940145 10.9010812 3.864946510.00027899 0.02440633 0.2722144 210773_s_at FPRL1 1.096511 8.06563753.86209224 0.0002816 0.02456545 0.26372575 204620_s_at CSPG2 1.0955692710.356296 3.85613369 0.00028713 0.02491902 0.24601655 227067_x_atNOTCH2NL 1.0532533 10.0530487 3.85320299 0.00028989 0.025078680.23731212 226368_at CHST11 1.07195471 9.52648879 3.8487656 0.000294110.02532955 0.22413996 213142_x_at LOC54103 1.06311548 10.42118153.84869575 0.00029418 0.02532955 0.22393268 217992_s_at EFHD2 1.0650685611.6374518 3.84358776 0.00029911 0.02567362 0.20878091 221571_at TRAF31.06383739 9.65844518 3.84232271 0.00030035 0.02570473 0.20503022225207_at PDK4 1.13997001 6.99602651 3.84205117 0.00030061 0.025704730.20422522 201191_at PITPNA 1.07930886 8.54956136 3.83764717 0.000304950.02584057 0.19117405 219412_at RAB38 1.09786171 8.08626906 3.834421240.00030817 0.02600194 0.18161959 50221_at TFEB 1.06697604 9.578325833.83038439 0.00031224 0.02622405 0.16966997 206140_at LHX2 1.065745699.81614566 3.82420766 0.00031857 0.02659987 0.15140014 226545_at CD1091.07280592 9.51243783 3.82411952 0.00031866 0.02659987 0.151139541552486_s_a LACTB 1.08525899 8.38629859 3.82306652 0.00031975 0.02665030.1480267 228368_at ARHGAP2O 1.14164081 7.83168691 3.81871004 0.000324310.02696861 0.13515348 238727_at LOC440934 1.11497925 7.086206453.8125927 0.00033081 0.02730892 0.11709143 225283_at ARRDC4 1.049690359.71669678 3.8080796 0.00033569 0.02759937 0.10377692 201995_at EXT11.09076481 6.49400167 3.80540237 0.00033861 0.02779804 0.09588293231496_at FCAMR 1.09935645 7.04227829 3.79899562 0.00034571 0.028295830.07700546 217741_s_at ZFAND5 1.03867699 11.247246 3.79602954 0.000349040.02848348 0.06827223 226075_at SPSB1 1.09367375 6.41796675 3.791317980.0003544 0.02879199 0.0544079 1569136_at MGAT4A 1.18908532 6.306079133.78721234 0.00035914 0.02909023 0.04233483 AFFX-HUMIS

STAT1 1.06320305 9.76660865 3.78614824 0.00036038 0.02914726 0.03920699206157_at PTX3 1.13951692 9.77811771 3.77291403 0.00037611 0.029983890.00034936 204899_s_at SAP30 1.05454489 9.10790083 3.7723175 0.000376830.02998389 −0.0014002 210427_x_at ANXA2 1.07331631 12.5352054 3.772027070.00037719 0.02398389 −0.002252 210357_s_at SMOX 1.08311104 8.039670093.7719322 0.0003773 0.02998389 −0.0025302 225530_at MOBKL2A 1.0439155210.5141996 3.76923042 0.0003806 0.03009487 −0.010452 234976_x_at SLC4A51.0654205 8.11158064 3.76817676 0.0003819 0.03011937 −0.0135404225115_at HIPK2 1.08936992 8.35503513 3.76532698 0.00038542 0.03026716−0.0218911 212561_at RAB6IP1 1.05486737 10.6169658 3.76463655 0.000386280.03026716 −0.0239136 233177_s_at PNKD 1.05881097 8.90692004 3.76033180.00039167 0.03054886 −0.0365193 205926_at IL27RA 1.08811794 8.500829493.75788045 0.00039478 0.03074707 −0.0436938 203940_s_at VASH1 1.102050978.93929781 3.75557481 0.00039772 0.03085591 −0.0504392 230634_x_atLOC113179 1.06907966 7.85469698 3.75508795 0.00039834 0.03085591−0.0518633 219994_at APBB1IP 1.07862342 8.79352106 3.75501728 0.000398430.03085591 −0.05207 211139_s_at NAB1 1.07131493 8.72031957 3.746469370.00040954 0.0314976 −0.0770544 201707_at PEX19 1.04709872 10.57484713.74254693 0.00041473 0.03166964 −0.0885078 209933_s_at CD300A1.06497364 9.72572801 3.74177958 0.00041576 0.03168935 −0.0907476203233_at IL4R 1.07541642 8.96600019 3.74112983 0.00041662 0.03168935−0.092644 212724_at RND3 1.10102105 7.85276337 3.73595709 0.00042360.03207812 −0.1077338 218260_at C19ORF58 1.05658126 9.528519853.72698571 0.00043597 0.03278903 −0.1338755 202779_s_at UBE2S /// L

1.03653716 12.7522175 3.71585925 0.00045179 0.03383761 −0.1662444204589_at NUAK1 1.08993672 6.70389618 3.71372502 0.00045488 0.0339596−0.1724466 200078_s_at ATP6V0B 1.0264003 13.5385773 3.71309911 0.00045580.0339596 −0.1742651 202192_s_at GAS7 1.07358071 9.32496946 3.713027120.0004559 0.0339596 −0.1744742 242705_x_at — 1.050541 9.417488823.71038947 0.00045976 0.03410795 −0.1821356 218611_at IER5 1.0704002111.1112341 3.70562135 0.00046683 0.0343816 −0.1959768 239598_s_at AYTL11.0605954 9.78054544 3.70535414 0.00046723 0.0343816 −0.1967522219456_s_at RIN3 1.07330011 7.90448799 3.70257871 0.00047139 0.03464126−0.2048036 211572_s_at SLC23A2 1.07618941 7.04729666 3.701420120.00047314 0.03470886 −0.2081635 212502_at C10ORF22 1.043076489.95312582 3.70033342 0.00047478 0.03475049 −0.2113144 201251_at PKM21.04329421 13.0859336 3.69894945 0.00047688 0.03485776 −0.2153264204135_at DOC1 1.07274599 8.83386998 3.69578905 0.00048172 0.03516424−0.2244847 219944_at RSNL2 1.08504226 7.05512921 3.69481629 0.000483220.03517085 −0.2273027 210018_x_at MALT1 1.06841222 7.99947523 3.693893290.00048464 0.03517085 −0.229976 236220_at — 1.14920843 4.264923243.69312582 0.00048583 0.03517085 −0.2321986 213935_at ABHD5 1.078226086.87154542 3.69294217 0.00048612 0.03517085 −0.2327305 227420_atTNFAIP8L1 1.06654551 8.06189779 3.69281506 0.00048631 0.03517085−0.2330985 219496_at ANKRD57 1.13993106 6.53387141 3.6910586 0.000489050.03532176 −0.2381839 214743_at CUTL1 1.06965625 9.94412122 3.687912660.00049398 0.0355839 −0.2472886 1554544_a_a MBP 1.07318708 10.16075243.6870054 0.00049541 0.03564002 −0.2499134 218614_at C12ORF35 1.0669134810.0756991 3.68269534 0.00050226 0.03608547 −0.2623776 205147_x_at NCF41.03578282 11.8404339 3.6799098 0.00050674 0.03617329 −0.2704283223852_s_at STK40 1.07352861 8.47342374 3.67987641 0.00050679 0.03617329−0.2705248 204834_at FGL2 1.15453451 8.63307396 3.67701847 0.000511420.03645638 −0.2787809 36994_at ATP6V0C 1.03052612 13.09078 3.67584670.00051333 0.03649744 −0.2821648 1555168_a_a CALN1 1.07042924 7.37894213.66717734 0.00052769 0.03716608 −0.3071804 203388_at ARRB2 1.057649419.38740578 3.66559438 0.00053035 0.03717544 −0.3117441 214054_at DOK21.07678197 11.2259885 3.66223375 0.00053604 0.03752644 −0.321429212096_s_at MTUS1 1.11473269 7.49260762 3.6528896 0.00055218 0.03845937−0.3483291 225480_at C1ORF122 1.04930018 10.1940995 3.650800130.00055586 0.03866588 −0.3543385 201700_at CCND3 1.04752925 12.89295743.64778851 0.00056119 0.03888847 −0.3629964 218399_s_at CDCA4 1.0386582610.9812294 3.64588211 0.00056459 0.03907466 −0.3684747 212003_atC1ORF144 1.05223728 9.96851324 3.64185086 0.00057185 0.03942724−0.3800532 205099_s_at CCR1 1.07264855 9.06024264 3.63132179 0.000591230.04045726 −0.4102577 201422_at IFI30 1.05859805 11.1928984 3.630124470.00059347 0.04050934 −0.413689 227220_at NFXL1 1.06892434 8.691717223.62491347 0.00060333 0.04097752 −0.4286146 213923_at RAP2B 1.0518156211.5158708 3.62050346 0.00061179 0.04138559 −0.4412357 242538_at TFDP11.06598341 8.25495776 3.61714555 0.00061831 0.04163319 −0.4508394211855_s_at SLC25A14 1.04783376 8.87468082 3.61205543 0.000628320.04220328 −0.4653867 205462_s_at HPCAL1 1.0537572 10.6818738 3.606697920.00063902 0.04273699 −0.4806845 213649_at SFRS7 1.10439275 9.366017543.60651451 0.00063939 0.04273699 −0.4812079 225701_at AKNA 1.0526028.96472073 3.60207226 0.00064841 0.04315666 −0.4938812 217691_x_atSLC16A3 1.06195853 9.25873814 3.60186431 0.00064883 0.04315666−0.4944742 225375_at C17ORF32 1.04600249 10.3975791 3.599583710.00065351 0.04336219 −0.5009765 206710_s_at EPB41L3 1.105965857.40730158 3.59798029 0.00065681 0.04347608 −0.5055465 204393_s_at ACPP1.05975941 8.04387684 3.59438387 0.00066429 0.04381176 −0.5157924244536_at TP53BP2 1.18627513 7.50015327 3.58918064 0.00067525 0.04421781−0.5306045 219183_s_at PSCD4 1.04907356 10.1644303 3.58716888 0.000679530.04438865 −0.5363279 226267_at JDP2 1.0662635 8.31398002 3.58283490.00068885 0.04454185 −0.548651 202111_at SLC4A2 1.06505371 9.071298283.58192152 0.00069082 0.04454185 −0.5512469 205128_x_at PTGS1 1.0556977310.4322081 3.58162573 0.00069147 0.04454185 −0.5520875 227107_at —1.05069658 9.99172727 3.57890951 0.00069739 0.0448057 −0.5598043204489_s_at CD44 1.06303314 10.62276 3.57845421 0.00069838 0.04481711−0.5610975 224733_at CMTM3 1.05905507 10.6346875 3.57586316 0.000704090.04507716 −0.5684547 229045_at SLIC1 1.07967634 7.89386361 3.572333150.00071192 0.04541946 −0.5784727 242414_at QPRT 1.05189094 10.24631663.56946163 0.00071836 0.04561726 −0.5866174 227948_at FGD4 1.091618687.2001949 3.55996253 0.00074006 0.04665922 −0.6135311 207610_s_at EMR21.10912425 6.51140397 3.55918695 0.00074185 0.04665922 −0.6157265238389_s_at — 1.08307842 8.36785016 3.55808073 0.00074443 0.04672969−0.6188574 202295_s_at CTSH 1.0545204 12.0343467 3.55490548 0.000751860.04706777 −0.6278407 213134_x_at BTG3 1.04181201 11.0553855 3.553296580.00075565 0.04706777 −0.6323906 204495_s_at C15ORF39 1.060732239.19429662 3.55321693 0.00075584 0.04706777 −0.6326159 225631_atKIAA1706 1.09137745 7.01050123 3.55021925 0.00076296 0.04734911−0.6410896 217168_s_at HERPUD1 1.03983791 11.6835542 3.546643590.00077153 0.04764859 −0.6511914 203658_at SLC25A20 1.045614799.46245075 3.54654461 0.00077177 0.04764859 −0.6514709 226735_atFLJ90013 1.05055665 9.2921795 3.54448273 0.00077675 0.04781967 −0.657293212372_at MYH10 1.06171907 9.0082261 3.53720879 0.00079459 0.04864948−0.6778151 214769_at — 1.06476746 8.52685941 3.53521138 0.000799550.04873518 −0.6834457 225408_at MBP 1.0628553 8.95772417 3.534153790.00080219 0.04881373 −0.6864262 222900_at — 1.05686661 9.967199593.53260926 0.00080606 0.04891403 −0.690778 1562475_at DKFZP686O11.08348486 8.1338617 3.53084868 0.0008105 0.04912864 −0.6957371226629_at SLC43A2 1.09818747 7.92209671 3.5269652 0.00082036 0.04956322−0.7066702 204174_at ALOX5AP 1.04445917 12.5979593 3.52653085 0.000821470.04956322 −0.7078925 211067_s_at GAS7 1.06066251 9.58135451 3.526296940.00082207 0.04956322 −0.7085508 204157_s_at KIAA0999 1.060204928.89537432 3.52624693 0.0008222 0.04956322 −0.7086915 211026_s_at MGLL1.05773402 7.85103089 3.52322146 0.00082998 0.04986733 −0.7172027204614_at SERPINB2 −1.1647768 12.4744252 −7.4528925 4.60E−10 9.68E−0712.5679641 211421_s_at RET −1.1345252 9.80328848 −7.1113218 1.75E−093.41E−06 11.3371247 207725_at POU4F2 −1.1644052 9.97790101 −6.93397073.49E−09 6.15E−06 10.6980464 208206_s_at RASGRP2 −1.1124445 10.5120774−6.549181 1.56E−08 1.82E−05 9.31420762 218971_s_at HSPC049 −1.15023669.26509596 −6.353404 3.32E−08 3.04E−05 8.6128924 222799_at HSPC049−1.1678019 8.76549992 −6.2405739 5.13E−08 4.25E−05 8.20995923 219463_atC20ORF103 −1.1066514 11.1578088 −6.1792066 6.49E−08 5.22E−05 7.99126082218858_at DEPDC6 −1.1739709 8.39313128 −6.1048654 8.64E−08 6.72E−057.72680015 214539_at SERPINB10 −1.1393961 9.05047781 −6.0524221 1.06E−077.91E−05 7.54057412 225510_at OAF −1.0795282 10.1352866 −5.90102981.88E−07 0.00012109 7.0047035 228855_at LOC645919 −1.1276666 10.7515984−5.8846827 2.00E−07 0.0001259 6.94700615 200799_at HSPA1A −1.094616210.8594511 −5.7859004 2.92E−07 0.00016854 6.59909626 206643_at HAL−1.1136035 9.45516733 −5.7636924 3.17E−07 0.000177 6.52106329 44790_s_atC13ORF18 −1.1118604 11.1923769 −5.7586514 3.23E−07 0.00017859 6.50336066202441_at SPFH1 −1.0851805 11.4291926 −5.6315658 5.23E−07 0.000255216.05830953 206034_at SERPINB8 −1.080288 10.6134257 −5.5518212 7.06E−070.00032156 5.78034465 203685_at BCL2 −1.1572394 9.68186938 −5.53443397.53E−07 0.00034041 5.71987917 216733_s_at GATM −1.0919977 10.6962606−5.5025531 8.49E−07 0.00037436 5.60914785 224428_s_at CDCA7 −1.072326111.8097904 −5.4896239 8.91E−07 0.0003867 5.56429181 201310_s_at C5ORF13−1.1126729 11.785614 −5.4263444 1.13E−06 0.00045596 5.34518848 213361_atTDRD7 −1.1610606 10.9747672 −5.391919 1.28E−06 0.00050496 5.22630402219714_s_at CACNA2D3 −1.0949691 10.9314712 −5.3685146 1.40E−060.00054258 5.14560908 35974_at LRMP −1.1227255 8.47924836 −5.31813011.69E−06 0.00062826 4.97225553 201309_x_at C5ORF13 −1.1203829 9.89153948−5.2776918 1.96E−06 0.00070587 4.83349392 243824_at — −1.18267178.98902905 −5.2561294 2.13E−06 0.00073085 4.75964206 226117_at TIFA−1.0706362 10.6431699 −5.2203927 2.43E−06 0.0008154 4.63745968210986_s_at TPM1 −1.0953979 11.1982 −5.1779859 2.84E−06 0.000901454.49283173 235275_at OXCT2 −1.167218 12.4747234 −5.1258467 3.43E−060.0010376 4.31556088 203178_at GATM −1.1772979 9.84150408 −5.08269864.02E−06 0.00116392 4.16933171 223062_s_at PSAT1 −1.0966737 10.8142971−5.0731123 4.17E−06 0.00119913 4.13690304 227921_at — −1.09392129.03183919 −5.0296725 4.88E−06 0.00137633 3.99023064 225673_at MYADM−1.0710199 12.4026311 −5.0110829 5.23E−06 0.00143582 3.92760413210987_x_at TPM1 −1.0747681 11.0724469 −5.008451 5.28E−06 0.00144243.91874425 220252_x_at CXORF21 −1.1107929 11.2367599 −4.990621 5.63E−060.00153146 3.85876875 212175_s_at AK2 −1.0635824 12.0939996 −4.94796096.57E−06 0.00172797 3.71559637 213931_at ID2 /// ID2B −1.55758068.63155658 −4.8451866 9.53E−06 0.00231585 3.37261839 206116_s_at TPM1−1.0886322 10.541027 −4.8397732 9.72E−06 0.00235097 3.35463151 225421_atACY1L2 −1.1026709 10.2401371 −4.8246433 1.03E−05 0.00244373 3.30440211228188_at — −1.0980344 9.30046163 −4.8130876 1.07E−05 0.002520763.26608136 1553436_at MUC19 −1.1317348 7.84569387 −4.796243 1.14E−050.00260733 3.21028822 223165_s_at IHPK2 −1.0812006 8.49238402 −4.77441581.23E−05 0.00276466 3.13811043 217521_at — −1.0843722 8.45544985−4.7662509 1.27E−05 0.00282288 3.11114575 214787_at DENND4A −1.11303148.79367689 −4.743088 1.37E−05 0.00298199 3.03475381 212765_at CAMSAP1L1−1.0863982 9.42505575 −4.7345547 1.42E−05 0.0030621 3.00664977 210254_atMS4A3 −1.0500477 12.8157054 −4.7261168 1.46E−05 0.00314327 2.9788805233176_at — −1.1278256 8.19196857 −4.7198778 1.49E−05 0.003188882.95836149 223344_s_at MS4A7 −1.0542376 11.6140787 −4.6615341 1.84E−050.00376871 2.7670363 219951_s_at C20ORF12 −1.0986972 9.36939485−4.6610806 1.84E−05 0.00376871 2.76555328 224358_s_at MS4A7 −1.073780510.2934393 −4.6288589 2.06E−05 0.00414687 2.66033365 209822_s_at VLDLR−1.0809314 10.4822858 −4.6256973 2.09E−05 0.00417816 2.650026411554892_a_a MS4A3 −1.0607494 11.9760309 −4.6180329 2.14E−05 0.004277292.62505295 224916_at LOC340061 −1.0659077 11.5293213 −4.6084907 2.22E−050.00435798 2.59398619 219607_s_at MS4A4A −1.0618962 10.8982797−4.6084529 2.22E−05 0.00435798 2.59386325 220112_at ANKRD55 −1.08921088.61196167 −4.6022914 2.27E−05 0.00439877 2.57381817 202158_s_at CUGBP2−1.071327 10.2596168 −4.5821696 2.43E−05 0.00466718 2.50843969 229638_atIRX3 −1.0842058 12.4826855 −4.5731157 2.51E−05 0.00474087 2.479063911557359_at LOC285758 −1.0922204 9.92033734 −4.5727867 2.51E−050.00474087 2.47799688 1555037_a_a IDH1 −1.0626668 11.297782 −4.5627432.61E−05 0.00479572 2.4454411 235936_at LOC254559 −1.0942156 7.69992263−4.5533045 2.69E−05 0.0048917 2.41487632 217196_s_at CAMSAP1L1−1.0905855 8.32441354 −4.5428721 2.79E−05 0.0050078 2.38112639 225786_atLOC284702 −1.1841367 9.55400971 −4.510983 3.12E−05 0.00541251 2.27818048203221_at TLE1 −1.0725652 10.2194004 −4.504306 3.20E−05 0.005515872.25606737 218507_at HIG2 −1.0603259 10.2529741 −4.4729944 3.57E−050.0059656 2.1559794 223952_x_at DHRS9 −1.0842606 12.9366028 −4.44566273.92E−05 0.00631099 2.0683571 224929_at LOC340061 −1.0551654 11.6690807−4.4386464 4.02E−05 0.00644802 2.04590464 209485_s_at OSBPL1A −1.08325948.89666819 −4.4376043 4.04E−05 0.00645252 2.04257108 222369_at NAT11−1.0773853 9.63846481 −4.4294999 4.15E−05 0.00661759 2.01666018210279_at GPR18 −1.1061684 9.71898614 −4.4206221 4.28E−05 0.006765721.98830241 206542_s_at SMARCA2 −1.0665392 10.093152 −4.4164022 4.34E−050.00682612 1.97483232 228055_at NAPSB −1.1406853 10.0636876 −4.4114314.42E−05 0.00690524 1.95897232 206088_at LOC474170 −1.1642536 5.60881351−4.3987993 4.62E−05 0.00715313 1.91871021 1555728_a_a MS4A4A −1.061992810.814275 −4.3884831 4.79E−05 0.00739242 1.8858698 229159_at KIAA0960−1.1638873 7.81943811 −4.378427 4.96E−05 0.00756868 1.85389295212071_s_at SPTBN1 −1.0802737 10.3524809 −4.3710543 5.08E−05 0.007678311.83047131 224009_x_at DHRS9 −1.0883843 12.9995564 −4.3451551 5.56E−050.00815484 1.74834735 219471_at C13ORF18 −1.082994 11.244718 −4.34493945.56E−05 0.00815484 1.74766447 204674_at LRMP −1.0754387 9.48836985−4.3365053 5.73E−05 0.00835029 1.72097259 225594_at ZF −1.06609978.44053993 −4.3348185 5.76E−05 0.00835466 1.71563729 64900_at CHST5 ///A

−1.0783605 7.45420385 −4.3330734 5.80E−05 0.00836918 1.71011893218326_s_at LGR4 −1.1055698 7.35402657 −4.3327777 5.80E−05 0.008369181.70918383 204639_at ADA −1.0663173 8.71406105 −4.3311807 5.83E−050.00839318 1.70413466 220416_at ATP8B4 −1.0560097 10.8651277 −4.32887155.88E−05 0.00843796 1.69683558 226255_at ZBTB33 −1.056353 11.34447−4.3186727 6.09E−05 0.00862606 1.66462107 204548_at STAR −1.08289838.71225533 −4.3131689 6.21E−05 0.00876809 1.64725213 207865_s_at BMP8B−1.1309201 9.46800068 −4.3117307 6.24E−05 0.00878882 1.64271524244447_at KLF10 −1.3134824 7.8071422 −4.2828862 6.89E−05 0.009507071.55188213 224837_at FOXP1 −1.0552487 11.2859527 −4.279807 6.96E−050.00952643 1.54220361 201689_s_at TPD52 −1.0726713 9.3965084 −4.27400967.10E−05 0.00967829 1.52399041 212097_at CAV1 −1.0973744 8.37508938−4.2610503 7.42E−05 0.00997486 1.48332253 1557570_a_a LOC285084−1.0977131 8.27009497 −4.2541445 7.60E−05 0.01008195 1.46167694201690_s_at TPD52 −1.073115 10.5093023 −4.2504384 7.69E−05 0.010161041.45006755 214920_at KIAA0960 −1.1291766 9.28547078 −4.2405995 7.96E−050.01044325 1.41927233 226431_at ALS2CR13 −1.0804181 8.88019612−4.2395927 7.98E−05 0.01044325 1.4161231 227629_at PRLR −1.13851047.04094281 −4.2375147 8.04E−05 0.01046218 1.40962463 57540_at RBKS−1.0889358 8.11543924 −4.2362686 8.08E−05 0.01046218 1.40572847228455_at SLC16A4 −1.2438773 7.61141506 −4.2334573 8.15E−05 0.010493141.39694035 242511_at ST3GAL3 −1.0989987 7.9960706 −4.2291028 8.27E−050.01057053 1.38333428 225619_at SLAIN1 −1.1432234 8.6802401 −4.2271988.33E−05 0.01058985 1.37738486 213737_x_at GOLGA8G //

−1.0557244 13.4113502 −4.2214214 8.49E−05 0.01077515 1.35935067224486_s_at C15ORF41 −1.0809669 9.42072522 −4.2192321 8.56E−050.01083061 1.35251877 230480_at PIWIL4 −1.0659842 10.6705451 −4.21786498.60E−05 0.01085599 1.34825366 225224_at C20ORF112 −1.0767769 9.19255558−4.1971114 9.23E−05 0.01151643 1.28359413 219799_s_at DHRS9 −1.087354612.5296658 −4.1953591 9.28E−05 0.01155875 1.27814225 202979_s_at ZF−1.0920673 9.89384482 −4.1942804 9.31E−05 0.01157478 1.27478664206461_x_at MT1H −1.0392307 11.9250301 −4.1935006 9.34E−05 0.011579141.27236118 201675_at AKAP1 −1.0615779 10.8983992 −4.1859946 9.58E−050.01174461 1.24902648 227949_at PHACTR3 −1.0599385 10.7921228 −4.18083229.75E−05 0.01184572 1.2329899 237265_at C16ORF73 −1.0739194 9.90657205−4.1786481 9.82E−05 0.0118711 1.22620861 235758_at PNMA6A −1.06791428.36962585 −4.1782399 9.84E−05 0.0118711 1.22494122 1554298_a_a WDR49−1.168549 7.28424515 −4.1686361 0.00010161 0.01212964 1.19514511230008_at KIAA0960 −1.1023476 9.40901508 −4.156767 0.00010577 0.012436431.15837023 215771_x_at RET −1.0639479 8.73407172 −4.1514318 0.000107690.01258151 1.14185786 204301_at KBTBD11 −1.0665649 10.3597689 −4.14654230.00010949 0.01271022 1.12673448 201036_s_at HADH −1.0465759 10.8776177−4.1465262 0.00010949 0.01271022 1.12668456 223044_at SLC40A1 −1.07992658.72509702 −4.1435626 0.00011059 0.01281082 1.11752261 205996_s_at AK2−1.0533596 11.6545132 −4.1314862 0.00011519 0.01305473 1.08022438213894_at KIAA0960 −1.0975098 9.74897241 −4.1307312 0.000115490.01305473 1.07789445 235823_at LOC197322 −1.0867032 7.00344771−4.1303782 0.00011562 0.01305473 1.07680534 212593_s_at PDCD4 −1.07840759.6202895 −4.1277406 0.00011665 0.01305473 1.06866759 227254_at —−1.0878832 8.8387562 −4.1270419 0.00011693 0.01305473 1.06651244218082_s_at UBP1 −1.061315 11.2875622 −4.1236056 0.00011829 0.013172231.05591605 221648_s_at C1ORF121 −1.0625223 9.30594001 −4.11222940.00012291 0.01363084 1.02086816 225883_at ATG16L2 −1.0866743 8.95908959−4.1072117 0.000125 0.01380676 1.0054261 222388_s_at VPS35 −1.054410310.9995649 −4.096001 0.0001298 0.01425665 0.9709611 208636_at ACTN1−1.0393569 12.61059 −4.0933116 0.00013097 0.01432201 0.96270059204165_at WASF1 −1.0621996 10.2583762 −4.0742957 0.0001396 0.014946920.9043759 239963_at — −1.2400451 9.0375203 −4.0742228 0.000139630.01494692 0.9041527 227055_at METTL7B −1.0860464 10.9882916 −4.07330510.00014006 0.01494692 0.90134178 229700_at LOC148203 −1.07699849.16397658 −4.0732431 0.00014009 0.01494692 0.90115181 225720_at SYNPO2−1.093531 8.22812673 −4.0689427 0.00014212 0.01511757 0.88798401233782_at WDR68 −1.0892946 7.81601785 −4.0571162 0.00014785 0.015554690.85180964 226438_at MTBP −1.0674478 9.28796451 −4.0535202 0.000149640.01564376 0.84082167 200672_x_at SPTBN1 −1.0717572 7.97282842−4.0518568 0.00015048 0.01565768 0.83574084 228625_at CITED4 −1.066534312.4781742 −4.0414018 0.00015582 0.01601409 0.80383153 223704_s_at DMRT2−1.0966738 7.49852282 −4.038741 0.00015721 0.01612655 0.79571762223136_at AIG1 −1.0602864 11.4123181 −4.0340714 0.00015968 0.016348930.78148555 218168_s_at CABC1 −1.05636 10.9814373 −4.0298906 0.000161920.01654732 0.76875062 219056_at RNASEH2B −1.0587835 9.59474393−4.0293131 0.00016223 0.01654826 0.76699214 1553955_at LOC129285−1.0626958 9.65678818 −4.0249191 0.00016462 0.01676095 0.75361657216336_x_at MT1M −1.0417674 11.497183 −4.0083934 0.00017392 0.017577230.70338342 209007_s_at C1ORF63 −1.0860359 10.6932184 −4.00330330.00017689 0.01782313 0.68793375 204959_at MNDA −1.0681514 11.9635641−4.003101 0.00017701 0.01782313 0.68732013 232722_at RNASET2 −1.1219366.4751986 −3.9998645 0.00017892 0.0179496 0.67750249 201924_at AFF1−1.0636204 10.9900787 −3.9938919 0.0001825 0.01820614 0.65939689205268_s_at ADD2 −1.0749965 8.29295849 −3.9894046 0.00018524 0.018414520.64580364 217892_s_at LIMA1 −1.0674835 9.77391533 −3.9742552 0.000194770.0190165 0.59997453 225610_at UHRF2 −1.0478186 11.8006338 −3.97123630.00019673 0.01908993 0.5908533 213888_s_at TRAF3IP3 −1.073252210.3053256 −3.9709396 0.00019692 0.01908993 0.58995707 209879_at SELPLG−1.0891682 9.91966583 −3.9695775 0.00019781 0.0191422 0.58584343226630_at C14ORF106 −1.0672553 9.79100795 −3.961139 0.000203410.01964899 0.56037434 225455_at TADA1L −1.0580187 10.2337996 −3.95170120.00020985 0.02016419 0.5319252 1554352_s_a DENND4A −1.05904599.89217484 −3.9498502 0.00021113 0.02022705 0.52635021 227805_at —−1.0725811 7.97633184 −3.9486352 0.00021198 0.02022705 0.52269151204849_at TCFL5 −1.0508793 10.0777273 −3.9473794 0.00021286 0.020275640.51891058 212174_at AK2 −1.0435458 12.5602536 −3.9427886 0.000216110.02047123 0.50509441 243431_at BTBD14A −1.1988342 7.54359435 −3.93409680.00022239 0.02085605 0.4789607 1558027_s_a PRKAB2 −1.0672869 8.44162128−3.9261915 0.00022825 0.02129633 0.45522005 220615_s_at MLSTD1−1.0704751 11.0839465 −3.9246829 0.00022939 0.0213295 0.45069271220116_at KCNN2 −1.0475679 10.7237831 −3.9161743 0.00023589 0.021749680.42517604 201193_at IDH1 −1.0387181 11.9734806 −3.9122575 0.000238950.02199427 0.41344031 225782_at MSRB3 −1.0704 8.85357731 −3.91140570.00023962 0.02201882 0.41088889 218270_at MRPL24 −1.041775 10.7168033−3.9080124 0.0002423 0.02219357 0.40072844 1559139_at NOC2L −1.16140477.69426499 −3.9079762 0.00024233 0.02219357 0.4006202 201841_s_at HSPB1−1.0441743 13.4381243 −3.9073471 0.00024283 0.02220226 0.398736921569189_at TTC9C −1.1233947 6.22264013 −3.9060463 0.00024387 0.022260030.39484371 205944_s_at CLTCL1 −1.0767087 9.59502778 −3.8960537 0.0002520.0227332 0.36496078 218532_s_at FLJ20152 −1.0975951 7.14515674−3.8958965 0.00025213 0.0227332 0.36449103 205659_at HDAC9 −1.08057559.52806368 −3.8955883 0.00025238 0.0227332 0.36356988 228056_s_at NAPSB−1.133171 8.05318337 −3.8864469 0.00025006 0.02323287 0.33627243208158_s_at OSBPL1A −1.0689057 8.96913414 −3.8834664 0.0002626 0.02334620.32738037 241024_at C6ORF147 −1.130088 5.62544192 −3.8775071 0.000267770.02367801 0.30961257 212859_x_at MT1E −1.0360762 12.3752245 −3.87355210.00027126 0.02392114 0.29782945 219498_s_at BCL11A −1.07324928.13793041 −3.8714456 0.00027313 0.0240476 0.29155627 215095_at ESD−1.1487406 5.82227073 −3.8696858 0.00027471 0.02414738 0.28631705203253_s_at HISPPD1 −1.0681144 10.4329202 −3.8669778 0.000277150.02432282 0.2782577 213416_at ITGA4 −1.0669742 10.3810332 −3.86197710.00028171 0.02456545 0.26338338 1557283_a_a ZNF519 −1.10684145.33423642 −3.8586267 0.00028481 0.02479593 0.25342411 230424_at C5ORF13−1.129586 6.85369311 −3.8555889 0.00028764 0.02492377 0.24439825230550_at MS4A6A −1.0527231 11.5245536 −3.8469498 0.00029586 0.025433980.21875242 1555963_x_a B3GNT7 −1.0971417 7.71455009 −3.84177260.00030089 0.02570473 0.20339936 203518_at LYST −1.0508267 12.5285349−3.8410237 0.00030162 0.02572727 0.20117947 229084_at CNTN4 −1.10469248.60627464 −3.8396872 0.00030294 0.02579917 0.19721855 200912_s_atEIF4A2 −1.0342758 13.3848401 −3.8372855 0.00030531 0.02584057 0.19010257243514_at — −1.1677325 8.64926127 −3.834963 0.00030763 0.025996280.18322394 1560495_at — −1.0868663 7.91686834 −3.8289949 0.000313660.02626207 0.16555845 209539_at ARHGEF6 −1.0428012 11.4186716 −3.81847130.00032456 0.02696861 0.13444828 211980_at COL4A1 −1.0583579 8.52391992−3.8156429 0.00032755 0.02717595 0.1260953 222538_s_at APPL −1.05388959.69059359 −3.8135376 0.0003298 0.02730892 0.11988026 217540_at —−1.0829555 9.09428634 −3.8128923 0.00033049 0.02730892 0.11797567231950_at ZNF658 −1.0895471 8.18062639 −3.8089596 0.00033473 0.027562210.10637231 221900_at COL8A2 −1.0731684 10.4949814 −3.8010969 0.000343360.02814612 0.0831949 229033_s_at MUM1 −1.0955974 7.47621492 −3.7984490.00034632 0.02830357 0.0753956 201688_s_at TPD52 −1.0610401 9.71085633−3.7945851 0.00035068 0.02857425 0.0640208 209960_at HGF −1.12598555.57784014 −3.7926895 0.00035283 0.02870722 0.05844274 232232_s_atSLC22A16 −1.0425388 11.5170133 −3.785579 0.00036104 0.029157790.03753396 223470_at PIGM −1.0448041 10.782124 −3.7837211 0.000363210.02924694 0.03207456 218540_at THTPA −1.0678164 9.37118811 −3.7820580.00036517 0.02936123 0.0271889 226773_at — −1.0599901 8.73474937−3.7794255 0.00036829 0.02956841 0.0194579 238098_at — −1.11148475.09426112 −3.778084 0.00036989 0.02961164 0.01551954 217707_x_atSMARCA2 −1.0808866 10.5195127 −3.7780645 0.00036991 0.029611640.01546237 212993_at — −1.0777658 10.0764962 −3.7708097 0.000378670.03004896 −0.0058219 229123_at — −1.0812886 7.27161787 −3.76935560.00038045 0.03009487 −0.010085 235036_at LIX1L −1.0722631 8.44284176−3.7689888 0.0003809 0.03009487 −0.0111601 1557261_at WHDC1L1 //

−1.1135936 8.0995202 −3.7678412 0.00038231 0.03011937 −0.0145238228904_at HOXB3 −1.0881045 7.40156866 −3.7669423 0.00038342 0.03016331−0.0171583 201381_x_at CACYBP −1.0345348 12.6646023 −3.76138870.00039034 0.03049295 −0.0334251 224800_at WDFY1 −1.0460265 11.2146548−3.7556441 0.00039763 0.03085591 −0.0502365 228497_at SLC22A15−1.0528433 10.2806063 −3.7504565 0.00040432 0.03126767 −0.0654047218376_s_at MICAL1 −1.063991 10.8151846 −3.7464229 0.0004096 0.0314976−0.0771901 214997_at GOLGA1 −1.1629895 5.40289373 −3.7438471 0.0004130.03166964 −0.084712 232168_x_at MACF1 −1.1118803 7.19380131 −3.74364290.00041327 0.03166964 −0.0853084 215143_at FLJ36166 −1.14039435.25780477 −3.7428445 0.00041434 0.03166964 −0.0876391 229712_at SNAPC3−1.1504135 5.48415471 −3.7427571 0.00041445 0.03166964 −0.0878942208910_s_at C1QBP −1.0363862 12.212373 −3.7403131 0.00041772 0.03172049−0.0950274 223343_at MS4A7 −1.0576569 11.3702217 −3.7294854 0.000432490.03261559 −0.1265955 216007_at CLSTN2 −1.1573199 5.8326347 −3.72010110.00044569 0.03342695 −0.153911 218477_at TMEM14A −1.0520488 11.0359972−3.7120317 0.00045735 0.03401174 −0.1773659 225716_at — −1.048856912.276306 −3.711697 0.00045784 0.03401174 −0.1783381 229934_at —−1.1078549 9.5045234 −3.7090958 0.00046167 0.03418201 −0.1858919226020_s_at DAB1 /// O

−1.0604674 9.19536151 −3.7080794 0.00046317 0.03418201 −0.1888427231300_at LOC90835 −1.0706749 8.05881715 −3.7080185 0.000463260.03418201 −0.1890194 225431_x_at ACY1L2 −1.1051561 9.95149452−3.6951992 0.00048263 0.03517085 −0.2261934 239503_at — −1.10192416.4612666 −3.6931957 0.00048572 0.03517085 −0.2319963 208747_s_at C1S−1.0897058 7.74085712 −3.6813511 0.00050442 0.03616953 −0.2662632210658_s_at GGA2 −1.0464213 10.9126279 −3.6763333 0.00051254 0.03648841−0.2807596 207405_s_at RAD17 −1.0614693 9.75893285 −3.6739986 0.000516360.03662349 −0.2875005 218792_s_at BSPRY −1.0964707 7.1685673 −3.67007840.00052284 0.037029 −0.2988132 224838_at FOXP1 −1.0451305 11.003461−3.666886 0.00052818 0.03716608 −0.3080204 208956_x_at DUT −1.030557513.3123909 −3.6657787 0.00053004 0.03717544 −0.3112129 210375_at PTGER3−1.122068 4.90394615 −3.6657484 0.00053009 0.03717544 −0.3113002233252_s_at STRBP −1.0460631 9.42442497 −3.6597179 0.00054034 0.03777915−0.3286758 202309_at MTHFD1 −1.0363875 11.5356701 −3.6479618 0.000560880.03888847 −0.3624982 212510_at GPD1L −1.0564567 9.5177254 −3.64262940.00057044 0.03942724 −0.3778178 232242_at C3ORF14 −1.1397197 5.05025398−3.6421706 0.00057127 0.03942724 −0.3791352 203335_at PHYH −1.05090779.47404929 −3.6414392 0.00057259 0.03942897 −0.3812352 225876_at NPAL3−1.0545782 8.47639608 −3.6399342 0.00057533 0.03956752 −0.3855556226038_at LONRF1 −1.0686626 8.27265094 −3.6331772 0.00058777 0.04027091−0.4049391 241466_at MTL5 −1.0881094 7.2321193 −3.630577 0.000592620.04050197 −0.4123921 232702_at RABGAP1L −1.1084819 7.2641058 −3.6295590.00059453 0.04053125 −0.4153094 228157_at ZNF207 −1.1331898 9.20083267−3.628722 0.00059611 0.04058804 −0.4177074 220892_s_at PSAT1 −1.053976210.5575882 −3.6260997 0.00060107 0.04087498 −0.4252181 211987_at TOP2B−1.0376579 11.6916878 −3.6237021 0.00060564 0.04108363 −0.4320824207636_at SERPINI2 −1.1147369 8.32640727 −3.6221365 0.000608640.04123615 −0.4365631 1555702_a_a ST3GAL3 −1.0571721 11.469985−3.6202073 0.00061236 0.04138559 −0.4420828 208967_s_at AK2 −1.044400411.8885466 −3.6083697 0.00063567 0.04259196 −0.4759123 227233_at TSPAN2−1.0933291 4.88565746 −3.6039803 0.00064452 0.04297454 −0.4884391561488_at — −1.0791431 8.42185259 −3.5998639 0.00065293 0.04336219−0.5001777 232034_at LOC203274 −1.1061415 8.7194472 −3.59871 0.000655310.04342891 −0.5034667 210817_s_at CALCOCO2 −1.0381701 11.2547695−3.5973152 0.00065819 0.04351451 −0.5074419 208990_s_at HNRPH3−1.0433996 11.010468 −3.5949274 0.00066315 0.04378974 −0.5142443205550_s_at BRE −1.042758 10.1098377 −3.5935936 0.00066594 0.0438679−0.518043 218461_at ATPBD1C −1.044665 10.8560567 −3.588935 0.000675770.04421781 −0.5313034 203774_at MTR −1.0520755 1.5810662 −3.58877620.00067611 0.04421781 −0.5317553 1554791_a_a FLJ23861 −1.08028147.25343472 −3.5862528 0.00068149 0.0444105 −0.5389334 227662_at SYNPO2−1.0748437 9.18363146 −3.5850906 0.00068398 0.04451989 −0.5422384235374_at MDH1 −1.1308822 8.18431482 −3.584254 0.00068578 0.04454185−0.5446169 211929_at HNRPA3 −1.0599635 11.1782682 −3.5831072 0.000688260.04454185 −0.5478769 236421_at ANKRD45 −1.1046422 7.81492792 −3.58208890.00069046 0.04454185 −0.5507713 222428_s_at LARS −1.044671 11.3066627−3.5819545 0.00069075 0.04454185 −0.551153 218404_at SNX10 −1.054223910.5371703 −3.5819241 0.00069082 0.04454185 −0.5512396 225845_at ZBTB44−1.0510504 10.114137 −3.5792352 0.00069667 0.0448057 −0.5588792228030_at — −1.1453293 8.222179 −3.5744486 0.00070722 0.04522467−0.5724699 205543_at HSPA4L −1.0619155 10.0871911 −3.5711304 0.000714610.04550224 −0.5818846 222786_at CHST12 −1.0953465 8.08550285 −3.57100890.00071489 0.04550224 −0.5822293 226148_at ZBTB44 −1.044973 10.9431965−3.5699976 0.00071716 0.04559364 −0.5850975 220007_at METTL8 −1.07427387.97164029 −3.568486 0.00072056 0.04570388 −0.5893838 232049_at —−1.1055172 3.71843028 −3.5666355 0.00072475 0.04531638 −0.5946293225639_at SKAP2 −1.0513915 10.9430745 −3.5623166 0.00073462 0.04643409−0.6068655 201432_at CAT −1.029344 13.2389426 −3.5605892 0.000738610.04663198 −0.611757 243366_s_at CERKL −1.0677271 9.52062508 −3.55907610.00074211 0.04665922 −0.6160402 239163_at UBE2B −1.115315 5.28263677−3.5589302 0.00074245 0.04665922 −0.6164534 239911_at — −1.11573096.92640942 −3.5564148 0.00074832 0.04692001 −0.6235711 239841_at C7ORF24−1.1067027 8.40618863 −3.5537484 0.00075458 0.04706777 −0.6311131213510_x_at LOC220594 −1.0787105 9.26871882 −3.5532589 0.000755740.04706777 −0.6324971 203446_s_at OCRL −1.0590145 8.52928391 −3.55221680.00075821 0.04716146 −0.6354436 220900_at FLJ12078 −1.22428954.04470354 −3.550766 0.00076165 0.04732199 −0.6395446 222427_s_at LARS−1.0327116 11.8350021 −3.5464813 0.00077192 0.04764859 −0.6516498213908_at WHDC1L1 //

−1.106503 7.49688229 −3.54639 0.00077214 0.04764859 −0.6519076 235170_atZNF92 −1.0701713 10.4753161 −3.5440334 0.00077784 0.04781967 −0.6585616205804_s_at TRAF3IP3 −1.0645947 10.430865 −3.5397143 0.00078840.04837904 −0.6707492 227865_at C9ORF103 −1.0549476 9.09854389 −3.5375660.0007937 0.04864948 −0.6768078 201769_at CLINT1 −1.0404695 11.3472898−3.5358759 0.0007979 0.04872219 −0.6815728 1555962_at B3GNT7 −1.08163158.07026497 −3.5328566 0.00080544 0.04891403 −0.6900812 244050_at PTPLAD2−1.0466927 10.2444943 −3.5293148 0.00081438 0.04930933 −0.70005631554704_at ATP8B3 −1.0775601 9.03671576 −3.5253989 0.00082438 0.04963954−0.7110776

indicates data missing or illegible when filed

Polimunol and Copaxone Comparison: Differentially Expressed Pathways

In order to identify pathways differentially expressed by Polimunolcompared with Copaxone, the input probesets had to comply not only withthe conservative steps described above (resulting in a set of 779differentially expressed probesets), but also with a fold changethreshold of |FC|≧1.1. Pathway enrichment analysis employed the NIHDAVID platform, resulting in 137 pathways enriched among top probesetsupregulated by Polimunol relative to Copaxone®. Pathways significantlyenriched among top probesets differentially expressed between Polimunoland Copaxone in THP-1 cells are listed in Table 29.

TABLE 29 Pathways significantly enriched among top probesetsdifferentially expressed between Polimunol and Copaxone ® in THP-1cells. Fold Category Term Count Pvalue Enrichment BenjaminiGOTERM_BP_ALL GO: G009605~response to external stimulus 34 125E−124.242127482 2.13E−09 GOTERM_BP_ALL GO: 0050896~response to stimulus 661.47E−11 2.221777115 1.25E−08 GOTERM_BP_ALL GO: 0009611~response towounding 24 1.10E−10 5.226859162 6.26E−08 GOTERM_BP_ALL GO:0051239~regulation of multicellular organismal 30 2.86E−09 3.5464341111.22E−06 process GOTERM_BP_ALL GO: 0006950~response to stress 453.97E−09 2.52009281 1.35E−06 GOTERM_CC_ALL GO: 0005576~extracellularregion 32 1.62E−08 3.124422358 2.46E−06 GOTERM_BP_ALL GO: 0002376~immunesystem process 31 9.83E−09 3.264522306 2.79E−06 GOTERM_MF_ALL GO:0004888~transmembrane receptor activity 21 7.19E−08 4.277319182 9.08E−06GOTERM_MF_ALL GO: 0004872~receptor activity 30 6.09E−08 3.0990829351.15E−05 GOTERM_BP_ALL GO: 0006955~immune response 23 6.20E−083.925650193 1.51E−05 KEGG_PATHWAY hsa04060: Cytokine-cytokine receptorinteraction 14 2.08E−07 6.068719076 1.92E−05 GOTERM_MF_ALL GO:0004871~signal transducer activity 37 5.51E−08 2.648089319 2.09E−05GOTERM_MF_ALL GO: 0060089~molecular transducer activity 37 5.51E−082.648089319 2.09E−05 GOTERM_BP_ALL GO: 0006952~defense response 211.12E−07 4.15637457 2.37E−05 GOTERM_BP_ALL GO: 0032879~regulation oflocalization 22 1.58E−07 3.885957066 2.98E−05 GOTERM_MF_ALL GO:0030247~polysaccharide binding 10 4.26E−07 10.28108466 4.04E−05GOTERM_MF_ALL GO: 0001871~pattern binding 10 4.26E−07 10.281084664.04E−05 GOTERM_CC_ALL GO: 0005615~extracellular space 17 6.80E−074.626388691 5.17E−05 GOTERM_BP_ALL GO: 0048583~regulation of response tostimulus 19 3.08E−07 4.32390456 5.23E−05 GOTERM_CC_ALL GO:0044421~extracellular region part 19 2.56E−06 3.750331428 9.73E−05GOTERM_CC_ALL GO: 0005886~plasma membrane 51 1.99E−06 1.9185906040.00010059 GOTERM_BP_ALL GO: 0050794~regulation of cellular process 977.60E−07 1.431262036 0.00010778 GOTERM_BP_ALL GO: 0042127~regulation ofcell proliferation 25 8.88E−07 3.138545339 0.00010788 GOTERM_BP_ALL GO:0007166~cell surface receptor linked signal 30 8.25E−07 2.7370377370.000108 transduction GOTERM_BP_ALL GO: 0006954~inflammatory response 157.41E−07 5.299032363 0.0001146 GOTERM_BP_ALL GO: 0042221~response tochemical stimulus 33 1.27E−06 2.509579282 0.00013487 GOTERM_BP_ALL GO:0050789~regulation of biological process 99 1.24E−06 1.4051333610.00014066 GOTERM_BP_ALL GO: 0065007~biological regulation 101 2.61E−061.374157191 0.00023327 GOTERM_BP_ALL GO: 0048584~positive regulation ofresponse to stimulus 13 2.38E−06 5.72397892 0.00023849 GOTERM_BP_ALL GO:0002684~positive regulation of immune system 13 2.57E−06 5.6827992150.00024311 process GOTERM_BP_ALL GO: 0001568~blood vessel development 134.31E−06 5.410336239 0.00036654 GOTERM_BP_ALL GO: 0001944~vasculaturedevelopment 13 4.97E−06 5.337223587 0.00038399 GOTERM_BP_ALL GO:0042060~wound healing 11 4.89E−06 6.683846154 0.00039593 GOTERM_BP_ALLGO: 0048519~negative regulation of biological process 41 6.21E−062.055488241 0.00040825 GOTERM_BP_ALL GO: 0048514~blood vesselmorphogenesis 12 6.15E−06 5.786879787 0.00041817 GOTERM_BP_ALL GO:0002682~regulation of immune system process 16 5.94E−06 4.1546829240.00042096 GOTERM_BP_ALL GO: 0007165~signal transduction 45 5.71E−061.96288636 0.00042219 GOTERM_BP_ALL GO: 0050793~regulation ofdevelopmental process 21 7.97E−06 3.166270454 0.0004676 GOTERM_BP_ALLGO: 0048731~system development 41 7.80E−06 2.037000612 0.00047369GOTERM_BP_ALL GO: 0050776~regulation of immune response 12 7.72E−065.652301187 0.00048624 GOTERM_BP_ALL GO: 0051240~positive regulation ofmulticellular 12 1.19E−05 5.401087801 0.0006771 organismal processGOTERM_BP_ALL GO: 0060341~regulation of cellular localization 112.31E−05 5.61667744 0.00126569 GOTERM_BP_ALL GO: 0032501~multicellularorganismal process 55 2.47E−05 1.69297015 0.00131208 GOTERM_BP_ALL GO:0002703~regulation of leukocyte mediated immunity 7 3.08E−05 11.19304380.00158406 GOTERM_MF_ALL GO: 0005539~glycosaminoglycan binding 82.69E−05 8.933908046 0.0020367 GOTERM_BP_ALL GO: 0048646~anatomicalstructure formation involved in 14 5.46E−05 3.902162058 0.00272943morphogenesis GOTERM_BP_ALL GO: 0043066~negative regulation of apoptosis15 8.17E−05 3.519048519 0.00396163 GOTERM_MF_ALL GO: 0001608~nucleotidereceptor activity, G-protein 5 6.34E−05 21.59027778 0.00399802 coupledGOTERM_MF_ALL GO: 0045028~purinergic nucleotide receptor activity, G- 56.34E−05 21.59027778 0.00399802 protein coupled GOTERM_BP_ALL GO:0043069~negative regulation of programmed cell 15 9.24E−05 3.478754070.00423954 death KEGG_PATHWAY hsa04610: Complement and coagulationcascades 6 9.31E−05 12.09974425 0.00427423 GOTERM_BP_ALL GO:0060548~negative regulation of cell death 15 9.63E−05 3.4655268690.00429948 GOTERM_BP_ALL GO: 0048856~anatomical structure development 419.18E−05 1.834500551 0.00433037 GOTERM_BP_ALL GO: 0001525~angiogenesis 90.00010467 6.076223776 0.00444135 GOTERM_BP_ALL GO: 0001819~positiveregulation of cytokine production 8 0.00010299 7.255192569 0.00448212GOTERM_BP_ALL GO: 0048660~regulation of smooth muscle cell 6 0.0001113912.15244755 0.00461078 proliferation GOTERM_BP_ALL GO: 0048518~positiveregulation of biological process 40 0.00011815 1.834331706 0.00477377GOTERM_BP_ALL GO: 0032502~developmental process 48 0.000130281.687839938 0.00514072 GOTERM_BP_ALL GO: 0007275~multicellularorganismal development 44 0.00014296 1.743991169 0.00551191GOTERM_BP_ALL GO: 0010033~response to organic substance 20 0.000148222.665010428 0.00558755 GOTERM_BP_ALL GO: 0009617~response to bacterium 90.00015325 5.756422525 0.0056515 GOTERM_MF_ALL GO: 0016502~nucleotidereceptor activity 5 0.00010797 19.0502451 0.00582884 GOTERM_MF_ALL GO:0001614~purinergic nucleotide receptor activity 5 0.00010797 19.05024510.00582884 GOTERM_BP_ALL GO: 0032496~response to lipopolysaccharide 70.00016853 8.339914987 0.00608127 GOTERM_BP_ALL GO: 0045765~regulationof angiogenesis 6 0.00017834 11.04767959 0.00630065 GOTERM_CC_ALL GO:0031226~intrinsic to plasma membrane 21 0.00020851 2.5197249960.00631924 GOTERM_BP_ALL GO: 0048513~organ development 31 0.000182952.027588128 0.00633147 GOTERM_BP_ALL GO: 0051707~response to otherorganism 11 0.00021593 4.312158809 0.00731991 GOTERM_BP_ALL GO:0051270~regulation of cell motion 10 0.00022302 4.78442817 0.00741176GOTERM_BP_ALL GO: 0031099~regeneration 6 0.00023762 10.416383620.00774377 GOTERM_MF_ALL GO: 0030246~carbohydrate binding 11 0.000176964.425336439 0.00834919 GOTERM_CC_ALL GO: 0005887~integral to plasmamembrane 20 0.00047736 2.436305529 0.01031444 GOTERM_BP_ALL GO:0030334~regulation of cell migration 9 0.00034868 5.110842429 0.01092533GOTERM_BP_ALL GO: 0051049~regulation of transport 13 0.000342693.464513557 0.01094009 GOTERM_BP_ALL GO: 0002237~response to molecule ofbacterial origin 7 0.00037883 7.209079057 0.01165013 GOTERM_BP_ALL GO:0007186~G-protein coupled receptor protein 13 0.00040141 3.4047805640.01170574 signaling pathway GOTERM_BP_ALL GO: 0002697~regulation ofimmune effector process 7 0.00041534 7.088927739 0.01170818GOTERM_CC_ALL GO: 0016020~membrane 82 0.00046587 1.342587724 0.01173539GOTERM_BP_ALL GO: 0002822~regulation of adaptive immune response 60.00039991 9.348036579 0.01186565 based on somatic recombination ofimmune receptors built from immunoglobulin superfamily domainsGOTERM_BP_ALL GO: 0009968~negative regulation of signal transduction 100.00041443 4.403060707 0.01187952 GOTERM_BP_ALL GO: 0044057~regulationof system process 10 0.00041443 4.403060707 0.01187952 GOTERM_BP_ALL GO:0051046~regulation of secretion 8 0.00039574 5.85660123 0.01195094GOTERM_BP_ALL GO: 0050778~positive regulation of immune response 80.00039574 5.85660123 0.01195094 GOTERM_BP_ALL GO: 0006935~chemotaxis 80.00045788 5.718798848 0.01248643 GOTERM_BP_ALL GO: 0042330~taxis 80.00045788 5.718798848 0.01248643 GOTERM_BP_ALL GO: 0002819~regulationof adaptive immune response 6 0.0004511 9.114335664 0.01250293GOTERM_BP_ALL GO: 0051101~regulation of DNA binding 8 0.000491755.652301187 0.01319259 GOTERM_BP_ALL GO: 0048523~negative regulation ofcellular process 34 0.00050059 1.834738973 0.01321981 GOTERM_BP_ALL GO:0009653~anatomical structure morphogenesis 24 0.00055741 2.160435120.01448509 GOTERM_BP_ALL GO: 0080134~regulation of response to stress 110.00057031 3.819340659 0.01459518 GOTERM_MF_ALL GO: 0019955~cytokinebinding 7 0.00035486 7.312836022 0.01483488 GOTERM_BP_ALL GO:0042981~regulation of apoptosis 22 0.00060362 2.254248281 0.01521241GOTERM_CC_ALL GO: 0031224~intrinsic to membrane 60 0.000857741.452927379 0.01617187 GOTERM_BP_ALL GO: 0040012~regulation oflocomotion 9 0.00067325 4.634407965 0.01670569 GOTERM_BP_ALL GO:0043067~regulation of programmed cell death 22 0.00068835 2.2316681650.0168318 GOTERM_BP_ALL GO: 0010941~regulation of cell death 220.0007188 2.224241649 0.01732135 GOTERM_BP_ALL GO: 0010648~negativeregulation of cell communication 10 0.00076041 4.050815851 0.01781109GOTERM_BP_ALL GO: 0001817~regulation of cytokine production 9 0.000752484.557167832 0.01787284 GOTERM_BP_ALL GO: 0030154~cell differentiation 280.00084605 1.942171983 0.01952917 GOTERM_BP_ALL GO: 0002460~adaptiveimmune response based on 6 0.00086878 7.925509273 0.01978057 somaticrecombination of immune receptors built from immunoglobulin superfamilydomains GOTERM_BP_ALL GO: 0002250~adaptive immune response 6 0.000868787.925509273 0.01978057 GOTERM_BP_ALL GO: 0065008~regulation ofbiological quality 27 0.00088955 1.969484297 0.01998171 GOTERM_BP_ALLGO: 0001775~cell activation 11 0.0009539 3.57424928 0.02059711GOTERM_BP_ALL GO: 0051223~regulation of protein transport 7 0.000951826.076223776 0.0208168 GOTERM_BP_ALL GO: 0048869~cellular developmentalprocess 29 0.00094798 1.89677599 0.02100365 KEGG_PATHWAY hsa04621:NOD-like receptor signaling pathway 7 0.00076766 6.125971143 0.02327548GOTERM_CC_ALL GO: 0033256~I-kappaB/NF-kappaB complex 3 0.0014085347.9647651 0.02352421 GOTERM_BP_ALL GO: 0002694~regulation of leukocyteactivation 8 0.0011427 4.910079819 0.02431771 GOTERM_BP_ALL GO:0050817~coagulation 6 0.00116213 7.440274012 0.02442105 GOTERM_BP_ALLGO: 0007596~blood coagulation 6 0.00116213 7.440274012 0.02442105GOTERM_BP_ALL GO: 0006916~anti-apoptosis 10 0.00120323 3.797639860.02466543 GOTERM_BP_ALL GO: 0009607~response to biotic stimulus 120.00120013 3.212100675 0.02490264 GOTERM_BP_ALL GO: 0008285~negativeregulation of cell proliferation 12 0.0012436 3.198012514 0.02517972GOTERM_MF_ALL GO: 0004930~G-protein coupled receptor activity 90.00068792 4.626488095 0.02574405 GOTERM_CC_ALL GO: 0009986~cell surface10 0.001793 3.5928663 0.02690939 GOTERM_BP_ALL GO: 0014070~response toorganic cyclic substance 7 0.00136752 5.671142191 0.02733082GOTERM_BP_ALL GO: 0040011~locomotion 12 0.00148086 3.1293856360.02888628 GOTERM_BP_ALL GO: 0070201~regulation of establishment ofprotein 7 0.0014651 5.596521899 0.02891444 localization GOTERM_BP_ALLGO: 0046649~lymphocyte activation 9 0.00154141 4.08104582 0.02971013GOTERM_BP_ALL GO: 0031328~positive regulation of cellular biosynthetic17 0.00162069 2.413453369 0.03052477 process GOTERM_BP_ALL GO:0050865~regulation of cell activation 8 0.00161108 4.62950383 0.03068591GOTERM_BP_ALL GO: 0007626~locomotory behavior 9 0.00169408 4.021030440.03119615 GOTERM_BP_ALL GO: 0070304~positive regulation ofstress-activated 4 0.0016835 16.2032634 0.03134323 protein kinasesignaling pathway GOTERM_BP_ALL GO: 0007599~hemostasis 6 0.001805676.751359751 0.03286331 GOTERM_BP_ALL GO: 0002706~regulation oflymphocyte mediated 5 0.00193607 9.206399661 0.03482477 immunityGOTERM_BP_ALL GO: 0009891~positive regulation of biosynthetic process 170.00195922 2.369169821 0.03486599 GOTERM_BP_ALL GO: 0008284~positiveregulation of cell proliferation 12 0.00206731 3.000604334 0.03637597GOTERM_BP_ALL GO: 0048522~positive regulation of cellular process 340.00209766 1.68922002 0.03652324 GOTERM_BP_ALL GO: 0043433~negativeregulation of transcription factor 5 0.00216669 8.9356232 0.03732224activity GOTERM_BP_ALL GO: 0051098~regulation of binding 8 0.002217144.379260379 0.03741874 GOTERM_BP_ALL GO: 0010646~regulation of cellcommunication 22 0.00220111 2.034656363 0.0375249 GOTERM_BP_ALL GO:0048568~embryonic organ development 7 0.0023046 5.124526076 0.03848637GOTERM_MF_ALL GO: 0004896~cytokine receptor activity 5 0.001364710.12044271 0.04596231 GOTERM_BP_ALL GO: 0045944~positive regulation oftranscription from 11 0.00298615 3.065984474 0.04864968 RNA polymeraseII promoter GOTERM_BP_ALL GO: 0043392~negative regulation of DNA binding5 0.00297111 8.211113211 0.04887781 GOTERM_CC_ALL GO: 0016021~integralto membrane 56 0.00368755 1.398972315 0.04976835 GOTERM_BP_ALL GO:0032880~regulation of protein localization 7 0.00309631 4.8333598220.04992419

These pathways include a variety of immune related pathways expected tobe relevant to Copaxone's mechanism of action, including immune-relatedpathways such as the cytokine-cytokine receptor interaction pathway(adjusted p<1.9e-5) that was also enriched among probesets modulated byCopaxone® (see above), and positive regulation of cytokine production(adjusted p<0.004). These pathways also include inflammation relatedpathways, such as inflammatory response (adjusted p<0.0001), NOD-likereceptor signaling (adjusted p<0.02), and response to lipopolysaccharide(adjusted p<0.006). The top 25 pathways are listed in Table 30, and thekey pathways are illustrated in FIG. 38. The specific genes in thecytokine-cytokine receptor interaction pathway are depicted in FIG. 39.

TABLE 30 Top 25 pathways significantly enriched among top probesetsdifferentially expressed between Polimunol and Copaxone AdjustedCategory Term Count p value GO Biological Process GO: 0009605~responseto external 34 2.13E−09 stimulus GO Biological Process GO:0050896~response to stimulus 66 1.25E−08 GO Biological Process GO:0009611~response to wounding 24 6.26E−08 GO Biological Process GO:0051239~regulation of 30 1.22E−06 multicellular organismal process GOBiological Process GO: 0006950~response to stress 45 1.35E−06 GOCellular GO:0005576~extracellular region 32 2.46E−06 Compartment GOBiological Process GO: 0002376~immune system 31 2.79E−06 process GOMolecular Function GO: 0004888~transmembrane 21 9.08E−06 receptoractivity GO Molecular Function GO: 0004872~receptor activity 30 1.15E−05GO Biological Process GO: 0006955~immune response 23 1.51E−05 KeggPathway hsa04060: Cytokine-cytokine 14 1.92E−05 receptor interaction GOMolecular Function GO: 0004871~signal transducer 37 2.09E−05 activity GOMolecular Function GO: 0060089~molecular transducer 37 2.09E−05 activityGO Biological Process GO: 0006952~defense response 21 2.37E−05 GOBiological Process GO: 0032879~regulation of 22 2.98E−05 localization GOMolecular Function GO: 0030247~polysaccharide 10 4.04E−05 binding GOMolecular Function GO: 0001871~pattern binding 10 4.04E−05 GO CellularGO: 0005615~extracellular space 17 5.17E−05 Compartment GO BiologicalProcess GO: 0048583~regulation of response 19 5.23E−05 to stimulus GOCellular GO: 0044421~extracellular region 19 9.73E−05 Compartment partGO Cellular GO: 0005886~plasma membrane 51 0.00010059 Compartment GOBiological Process GO: 0050794~regulation of cellular 97 0.000107777process GO Biological Process GO: 0042127~regulation of cell 250.000107884 proliferation GO Biological Process GO: 0007166~cell surfacereceptor 30 0.000108003 linked signal transduction GO Biological ProcessGO: 0006954~inflammatory 15 0.000114601 response

Polimunol and Copaxone Comparison: Discussion

Once demonstrated to be robustly designed as shown in the MoAsub-section, and upon applying conservative statistical approaches,hundreds of genes are differentially expressed in human monocytesfollowing activation with Polimunol compared to activation withCopaxone®. In and of itself, the fact that so many genes aredifferentially expressed immediately calls into question the “sameness”of Polimunol and suggests that its biological impact on human antigenpresenting cells differs significantly from Copaxone®. This stands insharp contrast to the lack of differences between the three differentlots of Copaxone tested in parallel, under blinding, in the sameexperiment (in the three possible pairwise comparisons between Copaxone®lots, for two of the comparisons zero significant probesets wereobserved, and for the third a single probeset passed FDR with adjusted pvalue of 0.044). Moreover, the fact that the differentially expressedgenes are enriched in key biological pathways such as “immune response”further supports the biological relevance of the observed differences.Finally, the fact that many of the pathways enriched among thedifferentially expressed genes are relevant to Copaxone's mechanism ofaction, such as cytokine-cytokine receptor interactions, and relevant topotential safety concerns, such as inflammatory response and response tolipopolysaccharide pathways, together raise serious concerns regardingthe safety and efficacy of Polimunol. In fact, the response tolipopolysaccharide pathway was also enriched among genes differentiallyexpressed by another purported generic, Probioglat (FIG. 40). Out of the137 pathways enriched among probesets upregulated by Polimunol relativeto Copaxone®, 37 of these pathways were also enriched in the priorcomparison with Probioglat (out of 64 total pathways seen forProbioglat). Of note, the introduction of Probioglat in Mexico wasassociated with a 3-fold increase in adverse events and a 7-foldincrease in relapses as detailed in Teva's seventh Citizen Petition(FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein).

Discussion Example 10-11

Copaxone® has long provided a safe and effective treatment option formultiple sclerosis patients, operating through a complex set ofmechanisms that have gradually been elucidated through extensiveresearch that continues to this day.

Methods for comparing two small molecule medicines to determinetherapeutic equivalence are well established, and standards forevaluating biologics are also rapidly becoming available. However, fornon-biological complex drugs (NBCDs) such as glatiramer acetate thelevel of evidence needed to determine equivalence remains an unresolvedquestion and a subject of ongoing research by the scientific community.Teva is an active participant in such research, conducting a steadyprogram of experiments to characterize Copaxone® and compare it tovarious glatiramoids marketed outside the United States and Europe aspurported generics. Such characterization studies are critical to ensurethat patients with multiple sclerosis (MS) continue to receive adequatemedicines that are efficacious and safe.

One key aspect of the public discourse on non-biological complex drugsconcerns the role of clinical trials. Well-controlled clinical trials ofappropriate duration (typically 2 years) using standard endpoints suchas annualized relapse rate (ARR) are an important means forinvestigating the safety and efficacy of medicines for MS, yet clinicalstudies not meeting those criteria distract from the essential questionof “sameness” and risk creating a false sense of security for apurported generic. In recent months, Synthon has publicly reportedclinical results for a follow-on glatiramoid purported to be a genericform of Copaxone, yet the trial results raise significant questionsregarding its validity [as detailed in Appendix 2 ofFDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein]. For instance, given the sample size of GATE(Copaxone=357, Placebo=84), the probability of showing any level ofannualized relapse rate (ARR) reduction (i.e. clinical efficacy) in thereference, well-established drug Copaxone®, using results from prioradequate, randomized, placebo-controlled studies with Copaxone® was high(>90%). Yet, a statistically unlikely result of no effect in reducingARR was recorded for the Copaxone® arm in the GATE study, attesting tothe lack of assay sensitivity. It is critical to know whether the trialhad assay sensitivity (i.e., could have distinguished an effective drugfrom an ineffective one). Thus, if the active control (Copaxone® in thecase of GATE study) had no effect at all in the trial (i.e., did nothave any of its well-established, expected effect), then finding even avery small difference between control and test drug is meaningless,providing no evidence that the test drug is effective. Lastly, the rateof adverse events leading to discontinuation was 2.4 fold higher in theSynthon product arm than in the Copaxone® arm (12 vs 5). Overall, themany shortcomings of the design and conduct of the GATE study render itsfindings unreliable.

Teva is continuously conducting experiments to further elucidateCopaxone®'s complex mechanism of action, and working towards thediscovery of validated biomarkers, which have yet to be identified. Tevathen seeks to compare Copaxone®'s profile to that of all purportedgenerics marketed globally. Synthon's Polimunol was recently introducedto clinical practice in Argentina, and has since been studied by Tevaextensively through a variety of characterization methods, eachproviding a small window into specific characteristics of this complexmedicine. For instance, genome-wide transcriptional studies wereemployed in carefully selected model systems informative of certainaspects of the biological impact of an immunological medicine. Tocompare the ex-vivo biological effect of Copaxone® and Polimunol inmouse lymphocytes following prior in vivo immunization, mousesplenocytes were utilized, which embody the key cell type impacted byantigenic presentation. Additionally, to compare the immediatebiological effects of Copaxone® and Polimunol in antigen-presentingcells, which are key to the mode of action of an antigen in mediatingT-helper cell immune response, a human monocyte (THP-1) cell line wasutilized. In both model systems significant differences in geneexpression profiles were detected between Copaxone and Polimunol,regardless of the immunization sequence or array randomization scheme.

In mouse splenocytes, the fact that significant and consistentdifferences in gene expression profiles are observed between splenocytesex-vivo activated with Polimunol and splenocytes activated withCopaxone®, regardless of whether the mice were initially in vivoimmunized with Copaxone or initially immunized with Polimunol, furtheremphasizes the robustness of the differences in biological impact ofthese two medicines on many genes. These hundreds of affected genesparticipate in immunologically relevant pathways and highlight potentialclinical implications of overly stimulated or under-regulatedimmunological mechanisms relevant to the response and well-being of MSpatients. For instance, IL18, which has been implicated in thepathogenesis of MS, is downregulated significantly less effectively byPolimunol than by Copaxone. IL18 is important for T helper celldifferentiation, and influences IFNg expression, suggesting that theimpact of each medicine on T cells (which play an important role inCopaxone's mechanism of action) is significantly different. Theimportance of IL18 via its actions in inducing Th1 responses (which isattributed, at least partially, to induction of IFNg production bynatural killer (NK) cells), was underscored in a study in the mousemodel of MS, autoimmune encephalomyelitis (EAE). Mice deficient for IL18were observed to be resistant to EAE, and treatment of these mice withIL18 restored the ability to generate a Th1 response, while treatment ofmice wild-type for IL18 increased EAE disease severity (Shi et al, J.Immunol., 2000). IL18 antibodies as well as the naturally expressed IL18inhibitor, IL18BP (which was upregulated by Copaxone treatment in thisstudy), have been proposed as potential therapeutic agents againstneuroinflammation (Felderhoff-Mueser et al, Trends Neurosci, 2005).

Similarly, key type I interferon pathway production pathway genesincluding RIG-I, MDA5, and IRF7 are all significantly upregulated byPolimunol relative to Copaxone®. This increased interferon signalingwith Polimunol treatment further increases concerns about possibleadverse events including flu-like symptoms in Polimunol-treatedpatients. As noted in Trinchieri et al, 2010, “IFN produced during viralinfection, other pathological conditions, or in the presence of DNAreleased by dying cells may mediate unwanted toxicity or inducepathological damage and inflammatory or autoimmune syndromes (Pascual etal., 2010).”

In human monocytes, many of the pathways enriched among the genesdifferentially expressed between Copaxone and Polimunol are relevant toCopaxone's mechanism of action (such as cytokine-cytokine receptorinteraction), and relevant to potential safety concerns (such asinflammatory response and response to lipopolysaccharide pathways). Thesame response to lipopolysaccharide pathway was also enriched amonggenes differentially expressed by another purported generic, Probioglat.This is particularly concerning because the introduction of anotherpurported generic to Copaxone, Probioglat in Mexico was associated witha 3-fold increase in adverse events and a 7-fold increase in relapses asdetailed in Teva's seventh Citizen Petition (FDA-2014-P-0933-0001available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein).

The gene expression findings suggest that regardless of the many issuesin the design and conduct of Synthon's GATE study that render theresults unreliable, the study itself was premature because it wasconducted on a glatiramoid that is almost certainly not equivalent toCopaxone®. Together, these data warrant further investigation, andemphasize the need for clinical trials following upon the establishmentof quality and pharmaceutical equivalence, specifically multi-yearsafety studies with standard clinical endpoints for MS, to ensure thesafety and well-being of multiple sclerosis patients.

How best to determine whether a differently manufactured glatiramoid isas safe and effective as Copaxone® remains an unresolved question thatis also the subject of active research. One such differentlymanufactured glatiramoid, Synthon's Polimunol, purports to have beentested in a clinical study (GATE), yet the trial results are ofquestionable validity and raise more questions than answers, as detailedin Appendix 2 of FDA-2014-P-0933-0001 available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein]. Beyond the extensive flaws in the design and conductof the GATE study that render the results unreliable, the study itselfwas premature because the equivalence of Synthon's glatiramoid withCopaxone® had not been conclusively established, and data from a fullbattery of high resolution physicochemical and gene expression studiessupport the conclusion that Sython's glatiramoid and Copaxone® are notequivalent.

The newest gene expression studies first reported in this document findextensive and significant differences between the gene expressionprofiles modulated by Synthon's Polimunol and the profiles modulated byCopaxone®, in both human monocytes and mouse splenocytes. Both of thesestudies employ a whole genome based approach, looking across the entireexpression array in an unbiased fashion, in model systems capturingdiffering, relevant aspects of Copaxone® effect.

In mouse splenocytes, 223 probesets were significantly differentiallyexpressed between Copaxone® and Polimunol in Copaxone®-immunized mice,and 431 probesets were significantly differentially expressed betweenCopaxone® and Polimunol in Polimunol-immunized mice. In bothimmunization conditions, IL18 was downregulated to a significantlygreater extent by Copaxone® than Polimunol, raising concerns aboutPolimunol's reduced effectiveness in suppressing this MS-associatedcytokine. As described above, IL18 is known to affect helper T celldifferentiation, an important aspect of Copaxone's mechanism of action,and to induce IFNg expression, and has been implicated in MSpathogenesis. IL18 induces proinflammatory Th1 responses and has beenimplicated in a number of neurodegenerative and neuroinflammatorycontexts including MS (Felderhoff-Mueser et al, Trends Neurosci, 2005).

The probesets differentially expressed between Copaxone® and Polimunolenriched to 22 pathways for Copaxone® immunization, and 10 pathways forPolimunol immunization. Many of these pathways overlapped, includingimmune response and response to virus. The fact that there are manysignificant differences between the gene expression patterns induced insplenocytes by Polimunol and Copaxone, regardless of whether thosesplenocytes are from mice immunized with Polimunol or with Copaxone®,further emphasizes the robustness of the observed differences betweenthese two medicines. Moreover, Polimunol upregulates a number ofinterferon-related genes, including RIG-I, MDA5, and IRF7, suggestingthe possibility of increased type I interferon signaling with Polimunoltreatment. An increase in type I interferon is concerning, and couldlead to possible adverse events such as flu-like symptoms.

In human monocytes, 779 probesets were differentially expressed, with137 pathways enriched among the probesets upregulated by Polimunolrelative to Copaxone®. Differentially expressed genes included CYP1B1and IL1B, and the pathways enriched among the differentially expressedprobesets included cytokine-cytokine receptor interactions and responseto lipopolysaccharide. The enrichment in the response tolipopolysaccharide (LPS) pathway is particularly concerning, because thesame prototypic pro-inflammatory pathway was also enriched among genesdifferentially expressed by the purported generic Probioglat, and theintroduction of Probioglat in Mexico was associated with a 3-foldincrease in adverse events (and a 7-fold increase in relapses) asdescribed in Teva's seventh Citizen Petition (FDA-2014-P-0933-0001available atwww.regulations.gov/#?documentDetail;D=FDA-2014-P-0933-0001, and alsodescribed herein). Whether a similar phenomenon potentially underliesthe higher adverse event rate (˜2.4-fold increase) observed in Synthon'sGATE trial warrants further investigation.

Taken together, the new data introduced here demonstrates that the genesand pathways modulated by Synthon's Polimunol differ significantly andextensively from those modulated by Copaxone®. These data are in linewith Teva's report of significant differences observed in variousstate-of-the-art physicochemical analyses detailed in a November commentto CP Docket FDA-2014-P-0933 (available atwww.noticeandcomment.com/FDA-2014-P-0933-fcol-41234.aspx).

The biology underlying the differences detailed herein provide potentialmechanistic hypotheses for differential efficacy and for the increase inadverse events leading to discontinuations as reported by Synthon withPolimunol relative to Copaxone® in the GATE study. Several strikingbiological differences stand out including levels of inflammatorycytokine genes such as IL18, interferon genes, and pro-inflammatorypathways such as response to lipopolysaccharide. These findings warrantfurther investigation, and raise substantial concerns for the safety andwell-being of patients treated with Synthon's Polimunol. The datafurther illustrates the imminent need for guidelines specific to NBCD,and specifically to glatiramoids. The gene expression changes describedin this document, together with physicochemical differences betweenPolimunol and Copaxone® described in a Nov. 13, 2014 comment to CPDocket FDA-2014-P-0933-0020 (available atwww.noticeandcomment.com/FDA-2014-P-0933-fcol-41234.aspx), support theconclusion that Synthon's Polimunol is not therapeutically equivalent orsimilar to Copaxone®.

More generally, to establish whether a follow on glatiramoid hascomparable safety and effectiveness to Copaxone®, it must first beestablished that the glatiramoid is the same as Copaxone® using a fullbattery of orthogonal methodologies including assays that detecthigh-resolution physicochemical properties and functionally relevantbiological properties, including genome-wide gene expression analyses inimmunologically relevant model systems including systems modelingantigen presenting cells and systems modeling T cells. Only when anapplicant has demonstrated equivalence on these biological andphysicochemical methods should they proceed to establish therapeuticcomparability through an adequately powered, at least 2-year clinicaltrial using a widely accepted clinical endpoint such as annualizedrelapse rate.

Example 12 Gene Expression Studies of a Human Monocyte Cell LineIdentify Dissimilarities Between Differently Manufactured Glatiramoids

Protein Levels at 24h are Consistent with Upregulation ofPro-Inflammatory mRNA Markers by Probioglat Versus GA Treatment at 6h

Protein concentration was tested in the same experiment at the 24htimepoint in order to validate upregulation of pro-inflammatory markersby Probioglat versus GA. Taking into consideration the fact thatdifferences observed at the mRNA level do not necessarily translate toprotein concentration differences, and may reflect regulatory processes,a Luminex kit measuring the concentrations of a panel of 45 chemokinesand cytokines (in pg/ml) was employed. The Bio-Plex Human Chemokine (BioRad kit) and the Luminex Performance Assay (R&D kit) were utilized.Protein concentrations were measured in a single replicate at 24 hours,a timepoint estimated to correspond to the time when the mRNA signalsobserved at 6 hours may have been translated to protein. Of the fivegenes tested by qRT-PCR, three were represented on the Luminex panel:CCL5, CXCL10, and MMP9. All three showed higher concentrations in theProbioglat samples than the GA samples (fold changes 1.5, 2.3, and 1.4,respectively; FIG. 45) consistent with the directionality of the geneexpression data (FIGS. 4A-D). Two other genes discussed above, IL10 andCCL2, were also present on the Luminex panel and also showed higherconcentration levels in Probioglat relative to GA (fold changes 1.8 and1.3, respectively; FIG. 45), consistent with the directionality observedat the mRNA level (FIG. 41d-e ).

Key Genes Upregulated by Probioglat Compared to GA were Validated inPrimary Human Monocytes

While immortalized cell lines are widely utilized in biological researchand provide various advantages including uniformity and accessibility,it is important to confirm that the changes introduced by theimmortalization process do not alter the key results. Therefore, topfindings from the expression data were further tested in primarymonocytes from healthy human donors using the sensitive method ofqRT-PCR. Nine genes (CCL2, CCL5, CXCL10, MMP1, MMP9, CD9, ICAM1, IL10,IL1RN) were chosen for testing based on the findings reported above fromthe THP-1 monocyte cell line. In primary monocytes from a healthy donorwith 6 replicates, the majority of the tested genes exhibited theexpected directionality of expression differences between Probioglat andGA. Five of these nine genes passed statistical significance (FIG. 42).These genes included IL1RN, and the pro-inflammatory CCL2, CCL5, CXCL10and MMP9 (p values<0.01 and 0.009, 0.029, 0.02, and 0.009,respectively).

Discussion Example 12

Protein concentrations tested in the same experiment at the 24htimepoint were consistent with the findings observed at the mRNA level,supporting the reported findings and indicating an inflammation-relatedbiological impact at the protein level. An independent follow-on studyin primary human monocytes tested nine inflammation and MS-related genesby qRT-PCR, finding that five of these genes were statisticallysignificantly upregulated by Probioglat relative to GA. These includedIL1RN, which is relevant to Copaxone mechanism of action. In addition,CCL2, CCL5, CXCL10, and MMP9 were all seen to be upregulatedsignificantly and consistently at both the mRNA and protein level inTHP-1 cells, as well as confirmed by qRT-PCR in primary human monocytes.These genes act in pro-inflammatory pathways and have been implicated asrelevant to MS susceptibility and severity, as described above.

The complex picture of genomic signatures described here underscores theintricate relationships between immune processes, effects of treatmenton the associated pathways and the differing responses of each immunecell type. Consistent with previous evidence from other systems and celltypes (Huang et al, Nucleic Acids Res. 2009), differences areconsistently observed between GA and differently-manufacturedglatiramoids, although their nature depends on the biological context ofthe tested model. Further, many of these differences affect moleculesrelevant to drug MOA and MS disease pathoetiology, particularly relatingto inflammatory signatures. Genes significantly upregulated byProbioglat relative to GA were significantly enriched for inflammatorypathways and included key pro-inflammatory genes.

These findings have identified significant differences that warrantfurther investigation, especially in light of the observed clinicaleffects of Probioglat's introduction. The Teva Patient Support Programin Mexico records numbers of adverse events, including during the years2012 and 2013 (Table 31; FIG. 46), for which a similar number ofpatients were tracked (1618 patients in 2012; 1552 in 2013). Probioglatwas first introduced in January 2013; subsequently, each time apatient's prescription was filled, it could be with either Probioglat orGA. In 2013 versus 2012 (during which only branded GA was marketed),numbers of adverse events, and relapses specifically, increased morethan 3-fold (from 125 to 380) and 7-fold (from 8 to 59), respectively(Table 31; FIG. 46), representing statistically-significant increases(p<2.2e-29 and p<3e-11, respectively). The gene-expression differencesobserved herein warrant careful investigation, through studies comparingGA to candidate generics in meaningful settings, most comprehensivelyincluding clinical trials.

TABLE 31 Reported Adverse Events and Relapses in Teva's Patient SupportProgram, 2012-2013. 2012 2013 Statistical Significance (Copaxone(Probioglat + of Increase alone) Copaxone) from 2012 to 2013 AdverseEvents 125 380 p < 2.2e−29* Adverse Event Rate 10.4 31.7 (per month)Relapses 8 59 p < 3e−11* Relapse Rate (per 0.7 4.9 month) Total Numberof 1618 1552 Patients in Teva's Patient Support Program *Single tailedp-value by Fisher's Exact test comparing the number of adverse eventsand relapses in 2012 < 2013.

Example 13 Validation of Key mRNA-Based Findings by Secreted ProteinAnalyses

To evaluate effects of Copaxone at the protein level, and assess theextent to which differences observed at the mRNA level (using micaroarryand qRT-PCR) were further consistent with effects observed at the levelof the translated proteins, levels of 42 secreted cytokines andchemokines were measured using Luminex technology, analyzing thesupernatant of THP-1 cells (human monocyte cell line) stimulated for 24hours with Copaxone, FOGA, or mannitol control.

After applying statistical significance threshold, Synthon's Polimunoltreatment increased the levels of 23 proteins (out of 39 havingsufficient measurements to test for this comparison) relative toCopaxone, while Probioglat treatment increased the levels of 31 proteins(out of 40 having sufficient measurements to test for this comparison)relative to Copaxone (Table 32).

Secreted Protein Analyses

Measurements were also undertaken at the protein level, in order toassess the biological relevance of the observed gene expressiondifferences. Levels of a panel of secreted cytokines and chemokines weremeasured via Luminex from THP-1 cells stimulated with branded GA,Polimunol, or Probioglat.

Cells from the THP-1 human monocyte cell line were incubated withbranded GA, FOGA (Polimunol or Probioglat), or vehicle control(mannitol) for 24 hours. This time point was chosen in order to reflecttranslation of mRNA expression patterns observed in the same studydesign at 6 hours post stimulation. Supernatants were collected andassayed for the concentration of selected proteins using a Luminexassay. A total of 5 biological replicates per condition were utilized.

Data (concentrations in pg/mL) were compared using a two-sided t-testwith equal variance, and corrected for multiple hypothesis testing usingBenjamini-Hochberg correction. To calculate the fold change between theprotein expression levels with FOGA and with GA, GA values were averagedtogether and compared to the average value for FOGA (average FOGAexpression level/average GA expression level).

Polimunol Versus Copaxone

Polimunol treatment significantly increased the levels of 23 proteins(out of 39 having sufficient measurements to test for this comparison).These include IFNg, TNFa, MIP-1a (CCL3), IL-8 (CXCL8), and IL-10 (FIG.47; adjusted p values as shown). Many of these proteins were alsoincreased in level by Copaxone treatment relative to mannitol control.Consistent with the result observed at the mRNA expression level,secreted levels of MMP-9, MCP-1 (CCL2), RANTES (CCL5), Gro-a (CXCL1),and IL-1b were increased with Polimunol treatment relative to GA (FIG.48; adjusted p values as shown). Of note, CCL2 was not modulated by GArelative to control, while it was increased by Polimunol treatmentrelative to GA.

A number of important differences in secreted protein level are observedfor Polimunol relative to Copaxone, including levels of IFNg, TNFa,IL-8, and MIP-1a. IFNg is the major cytokine that drives thepro-inflammatory Th1 T-cell response, and is both implicated in MS andknown to be relevant to Copaxone mechanism of action (Gilli et al 2012;Tumani et al 2011). TNFa is a major cytokine directing inflammatoryresponses, and polymorphisms in this gene have been reported toinfluence MS susceptibility (Rahmanian et al, 2014). The chemokine IL-8(CXCL8) has been implicated in MS disease progression and risk, andproposed as a biomarker for MS (Lund et al, 2004; Kelland et al, 2011;Almasi et al, 2013; Tomioka et al, 2014). MIP-1a (MacrophageInflammatory Protein 1-alpha; CCL3) is another proinflammatory chemokinewith relevance to MS (Zhang et al, Brain, 2000; Aung et al, 2010).

Differences are also observed in the level of secreted IL-10. IL-10 isan anti-inflammatory cytokine important for Th2 polarization, and hasbeen implicated in the mechanism of action of Copaxone (Vieira at al.Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell developmentand increased IL-10 production through modulation of dendritic cells. J.Immunol. 1950 170, 4483-4488 (2003); Kim, H. J. et al. Type 2 monocyteand microglia differentiation mediated by glatiramer acetate therapy inpatients with multiple sclerosis. J. Immunol. 1950 172, 7144-7153(2004); Weber, M. S. et al. Type II monocytes modulate T cell-mediatedcentral nervous system autoimmune disease. Nat. Med. 13, 935-943(2007)).

The observed differences in levels of each of these five proteins withPolimunol versus Copaxone treatment confirm the gene level reports bymicroarray as described (Kolitz et al, Sci Rep, 2015, in press). Asdetailed above, CCL2 and RANTES (CCL5) are inflammatory chemoattractantswith known relevance to MS (Allie et al 2005; Mahad et al 2006), andMMP-9 is a pro-inflammatory matrix metalloproteinase extensivelyimplicated in MS (Rosenberg 2005; Romme Christensen et al 2013;Kouwenhoven et al 2002; Waubant et al 2006; Milward et al 2008). Thebiological relevance of these genes is discussed at length in Section6.2. Gro-a (CXCL1) is another chemokine implicated in MS and MS models(Glabinski et al 1998; Rumble et al, J Exp Med, 2015), and IL-1b is aproinflammatory cytokine important for inflammasome signalling, withnumerous connections to MS in the literature (Prins et al 2013; Rossi etal 2014; Murta et al 2015).

Overall the proteomic data complements the microarray data and confirmsthe robustness of the detected signatures. These observationssubstantiate the concerns raised by upregulation of proinflammatorycytokines and associated pathways.

Probioglat Versus Copaxone

Key differences between Probioglat and Copaxone were identified usingmicroarray in THP-1 cells, then tested in primary monocytes, confirmingthe relevance of the cell line model. To see whether these geneexpression differences translated into differences at the protein level,indicating biological relevance, secreted protein levels were measuredfrom THP-1 cells treated with Copaxone or Probioglat.

Probioglat treatment significantly increased the levels of 31 proteins(out of 40 having sufficient measurements to test for this comparison).These include IFNg, TNFa, MIP-1a (CCL3), IL-8 (CXCL8), and IL-10 (FIG.49; adjusted p values as shown). The clear biological relevance of theseproteins to disease or to GA response is also described above. Many ofthese proteins were also increased in level by GA treatment relative tomannitol control. Consistent with results observed at the mRNAexpression level (Kolitz et al, Sci Rep 2015, in press), the 31 proteinsalso include MMP-9, IP-10 (CXCL10), MCP-1 (CCL2) and RANTES (CCL5) (FIG.50; adjusted p values as shown). Of note, CCL2 was not modulated by GArelative to control, while it was increased by Probioglat treatmentrelative to GA.

Secreted levels of several key proteins were observed to differ withProbioglat treatment relative to Copaxone, including IFNg, TNFa, IL-8,and MIP-1a. As discussed in the previous section, each of these geneshas important roles in inflammation and/or MS (Gilli et al 2012; Tumaniet al 2011; Rahmanian et al, 2014; Lund et al, 2004; Kelland et al,2011; Almasi et al, 2013; Tomioka et al, 2014; Zhang et al, Brain, 2000;Aung et al, 2010). The level of secreted IL-10 also differs betweenProbioglat and Copaxone treatment. As described in the previous section,IL-10 is an anti-inflammatory cytokine important for Th2 polarization,and implicated in Copaxone mechanism of action (Vieira at al. 2003; Kim,H. J. et al. 2004; Weber, M. S. et al. 2007).

As described above, CCL2, RANTES (CCL5) and IP-10 (CXCL10) are allinflammatory chemoattractants with relevance to MS (Allie et al 2005;Mahad et al 2006; Peperzak et al 2013; Thamilarasan et al 2013), andMMP-9 is a pro-inflammatory matrix metalloproteinase implicated in MS(Rosenberg 2005; Romme Christensen et al 2013; Kouwenhoven et al 2002;Waubant et al 2006; Milward et al 2008). As described inFDA-2014-P-0933; Kolitz et al, Sci Rep, 2015, in press; and above, thegenes coding for these proteins were also demonstrated to be induced todiffering degrees by Probioglat and Copaxone in both the THP-1 modelsystem and in primary human monocytes. The biological relevance of thesegenes is discussed at length above.

Thus, the protein analyses further supported the observation ofinflammation-related differences between Probioglat and Copaxone,consistent with the clinical observations of increased rates of adverseevents and relapses.

TABLE 32 Proteins and genes significantly differentially expressedbetween Polimunol and Copaxone ® treatment and between Probioglat andCopaxone ® treatment in THP-1 human monocytes. Polimunol vs CopaxoneProbioglat vs Copaxone Gene Benjamini Benjamini Protein symbol FC p.value p value FC p. value p value MIP-1a CCL3 1.37 3.59E−09 1.40E−071.56 1.58E−11 5.62E−10 MMP-9 MMP9 1.42 8.69E−09 1.69E−07 1.44 7.40E−093.70E−08 MDC CCL22 1.13 1.63E−07 2.12E−06 1.24 2.81E−11 5.62E−10 CCL24CCL24 1.15 2.39E−07 2.33E−06 1.25 2.31E−10 2.84E−09 CX3CL1 CX3CL1 1.282.28E−06 1.78E−05 1.64 3.15E−09 1.80E−08 MIP-3a CCL20 1.28 4.73E−062.65E−05 1.72 2.84E−10 2.84E−09 MCP-1 CCL2 1.16 4.75E−06 2.65E−05 1.262.48E−05 5.23E−05 TNF-a TNF 1.23 1.16E−05 5.64E−05 1.29 7.81E−072.08E−06 IL-8 IL8 1.21 2.40E−05 1.04E−04 1.30 6.39E−07 1.83E−06 MCP-4CCL13 1.21 4.98E−05 1.94E−04 1.44 2.66E−09 1.77E−08 RANTES CCL5 1.196.70E−05 2.38E−04 1.34 1.15E−08 5.13E−08 IL-1b IL1B 1.22 1.30E−044.22E−04 1.43 2.53E−07 8.44E−07 MCP-2 CCL8 1.19 1.76E−04 5.27E−04 1.507.15E−10 5.72E−09 IL-10 IL10 1.25 2.99E−04 8.34E−04 1.36 1.07E−052.53E−05 I-TAC CXCL11 1.21 8.60E−04 2.24E−03 1.40 3.03E−05 6.06E−05CXCL13 CXCL13 1.31 1.35E−03 3.25E−03 1.68 9.06E−08 3.30E−07 IP-10 CXCL101.28 1.42E−03 3.25E−03 1.64 5.88E−08 2.35E−07 MCP-3 CCL7 1.43 5.11E−031.11E−02 1.57 1.38E−03 2.21E−03 CCL1 CCL1 1.20 5.73E−03 1.18E−02 1.261.57E−03 2.35E−03 CXCL1 CXCL1 1.10 1.19E−02 2.32E−02 1.22 1.32E−052.93E−05 INF-g IFNg 1.18 1.32E−02 2.45E−02 1.42 1.05E−05 2.53E−05 CCL26CCL26 1.16 1.91E−02 3.39E−02 1.32 1.59E−03 2.35E−03 MIF MIF 1.232.86E−02 4.85E−02 1.38 5.54E−04 1.01E−03 IL-16 IL16 1.12 3.15E−025.13E−02 1.25 9.01E−05 1.72E−04 IL-6 IL6 1.19 3.37E−02 5.26E−02 1.331.06E−03 1.84E−03 CXCL6 CXCL6 1.18 4.02E−02 6.03E−02 1.16 6.56E−027.96E−02 TECK CCL25 1.11 5.67E−02 8.19E−02 1.44 3.77E−07 1.16E−06 GM-CSFCSF2 1.22 9.66E−02 1.35E−01 1.30 4.65E−02 5.81E−02 IL-2 IL2 1.161.11E−01 1.49E−01 1.34 1.20E−03 2.00E−03 MPIF-1 CCL23 1.05 2.48E−013.22E−01 1.02 6.91E−01 7.47E−01 MIP-3b CCL19 1.11 2.72E−01 3.42E−01 1.251.93E−02 2.57E−02 SDF-1a + b CXCL12 1.05 3.41E−01 4.15E−01 1.07 2.55E−012.92E−01 CXCL2 CXCL2 1.17 4.06E−01 4.80E−01 1.65 2.85E−03 4.07E−03 MIGCXCL9 1.07 4.43E−01 5.08E−01 1.31 5.46E−03 7.54E−03 CCL11 CCL11 0.994.61E−01 5.13E−01 1.00 8.61E−01 9.06E−01 CXCL5 CXCL5 0.93 5.16E−015.59E−01 0.79 3.05E−02 3.94E−02 MIP-1d (M

CCL15 0.97 5.45E−01 5.74E−01 1.00 9.22E−01 9.22E−01 SCYB16 CXCL16 1.016.77E−01 6.94E−01 1.02 5.44E−01 6.05E−01 CCL21 CCL21 1.01 8.27E−018.27E−01 1.00 8.96E−01 9.19E−01 IL-4 IL4 NA NA NA 1.26 1.62E−01 1.91E−01TARC CCL17 0.76 NA NA 1.39 NA NA CCL27 CCL27 NA NA NA NA NA NA

indicates data missing or illegible when filed

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1-100. (canceled)
 101. In a process for producing a drug productcomprising a glatiramer acetate related drug substance which involves anarray of testing, the improvement comprising including in the array oftesting the steps of: a) obtaining a batch of the glatiramer acetaterelated drug substance or drug product; b) contacting mammalian cellswith an amount of the glatiramer acetate related drug substance or drugproduct obtained in step a); c) determining the level expression of ABI2by the mammalian cells; and d) including the batch of the glatirameracetate related drug substance in the production of the drug product ifthe level of expression of is not substantially identical to the levelof expression of ABI2 by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions.102-149. (canceled)
 150. The process of claim 101, wherein contactingthe mammalian cells in step (b) comprises i) administering to a mammal apredetermined amount of glatiramer acetate related drug substance ordrug product of step (a), or ii) incubating the cells with an amount ofthe glatiramer acetate related drug substance or drug product of step(a), or a combination thereof; or contacting the mammalian cells in step(b) comprises i) administering to a mammal a predetermined amount ofglatiramer acetate related drug substance or drug product of step (a),or ii) incubating the cells with an amount of the glatiramer acetaterelated drug substance or drug product of step (a), or a combinationthereof, wherein the mammal is human and the cells are peripheralmononuclear blood cells, the predetermined time point is 0, 1, 2, or 3months or the incubation is for about 24 hours, for about 12 hours, orfor about 6 hours.
 151. The process of claim 101, wherein contacting themammalian cells in step (b) comprises i) administering to a mammal apredetermined amount of glatiramer acetate related drug substance ordrug product of step (a), and ii) obtaining cells from the mammal at oneor more predetermined time points; or contacting the mammalian cells instep (b) comprises i) administering to a mammal a predetermined amountof glatiramer acetate related drug substance or drug product of step(a), and ii) obtaining cells from the mammal at one or morepredetermined time points, wherein the mammal is human and the cells areperipheral mononuclear blood cells, the predetermined time point is 0,1, 2, or 3 months or the incubation is for about 24 hours, for about 12hours, or for about 6 hours.
 152. The process of claim 101, whereincontacting the mammalian cells in step (b) comprises incubatingmonocytic cell line cells with an amount of the glatiramer acetaterelated drug substance or drug product of step (a), therebycharacterizing the glatiramer acetate related drug substance or drugproduct of step (a); or contacting the mammalian cells in step (b)comprises incubating monocytic cell line cells with an amount of theglatiramer acetate related drug substance or drug product of step (a),thereby characterizing the glatiramer acetate related drug substance ordrug product of step a) wherein the mammalian cells are THE-1 cells orthe incubation is for about 24 hours, for about 12 hours, or for about 6hours.
 153. The process of claim 101, wherein contacting the mammaliancells in step (b) comprises i) immunizing a mammal with a predeterminedamount of glatiramer acetate related drug substance or drug product, ii)preparing a culture of cells from the mammal of step i) at one or morepredetermined time points after immunization, and iii) incubating cellsfrom the culture of cells obtained from the mammal with an amount of theglatiramer acetate related drug substance or drug product of step (a),thereby characterizing the glatiramer acetate related drug substance ordrug product of step (a); or contacting the mammalian cells in step (b)comprises i) immunizing a mammal with a predetermined amount ofglatiramer acetate related drug substance or drug product, ii) preparinga culture of cells from the mammal of step i) at one or morepredetermined time points after immunization, and iii) incubating cellsfrom the culture of cells obtained from the mammal with an amount of theglatiramer acetate related drug substance or drug product of step (a),thereby characterizing the glatiramer acetate related drug substance ordrug product of step (a), wherein the glatiramer acetate related drugsubstance or drug product of step (iii) is the same glatiramer acetaterelated drug substance or drug product of step (i), the glatirameracetate related drug substance or drug product of step (iii) is adifferent glatiramer acetate related drug substance or drug product ofstep (i), the incubation is for about 24 hours, for about 12 hours, orfor about 6 hours or the predetermined time point after immunization is3 days.
 154. The process of claim 101, wherein the contacting of step(b) is in a cell culture; wherein the contacting of step (b) is in acell culture and the culture is a primary culture; wherein thecontacting of step (b) is in a cell culture and the culture is a primaryculture, wherein the primary culture is a culture of spleen cells,wherein the primary culture is a culture of lymph node cells, or whereinthe primary culture of spleen cells is prepared about 3 days afterimmunization; wherein the contacting of step (b) is in a mammal; whereinthe contacting of step (b) is in a mammal and the mammal is a rodent orhuman; or wherein the mammal of step (b) is a rodent or human; whereinthe mammal of step (b) is a mouse; wherein the mammal of step (b) is amouse, wherein the mouse is a female (SJL X BALB/C) F1 mouse, andwherein the mouse is about 8 to 12 weeks old; wherein the cells of step(b) are of a type i) selected from the group of cell types consisting ofFoxP3+ T cells, regulatory T cells, natural killer T cells, T helper 2cells, CD8+ T cells, CD4+ T cells, B cells, macrophage cells, monocytecells, eosinophils, dendritic cells, granulocytes, megakaryocytes, andmyeloid progenitors; ii) selected from the group of cell typesidentified in Table 9; iii) selected from the group of cell typesidentified in Table 10; or iv) selected from the group of cell typesidentified in Table
 11. 155. The process of claim 101, wherein the levelof expression is determined in hematological cells; wherein the level ofexpression is determined in splenocytes; wherein the level of expressionis determined in monocytes; wherein the level of expression isdetermined in monocytes, and wherein the monocytes are THP-1; whereinthe level of expression is determined in peripheral blood mononuclearcells; or wherein the level of expression is determined in peripheralblond mononuclear cells and wherein the peripheral blood mononuclearcells are from a human.
 156. The process of claim 101, wherein the humanhas previously been treated with a glatiramer acetate related drugsubstance or drug product; wherein the human is a naïve; wherein thehuman is a glatiramoid naïve human; or wherein the human is afflictedwith RRMS.
 157. The process of claim 101, wherein the glatiramer acetaterelated drug substance or drug product is other than glatiramer acetatedrug substance or drug product; wherein the glatiramer acetate relateddrug substance is a glatiramoid or wherein the glatiramer acetaterelated drug product comprises a glatiramoid; wherein the glatirameracetate related drug substance is a glatiramoid other than glatirameracetate drug substance; or wherein the glatiramer acetate related drugproduct comprises a glatiramoid other than glatiramer acetate drugsubstance.
 158. In the process of claim 101 comprising step (d), if thelevel of expression of ABI2 is upregulated relative to the level ofexpression by the same type of cells in the absence of the glatirameracetate related drug substance under the same conditions, then includingthe batch of the glatiramer acetate related drug substance in theproduction of the drug product.
 159. The process of claim 101, whereinstep (c) further comprises i) determining the level of expression of atleast one gene of ABCF2, ACP6, AFG3L2, ALMS1, ARPC4, CALMS, CCDC64,CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC,HFE, IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2,SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13,UBAP2, VAV3, VDAC2, or ZFAND6; ii) determining the level of expressionof at least one gene of BIRC3, CCL24, CCR1, CISH, CSF1R, CX3CR1, CXCL10,HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG, IL7R, IL1RN, MMP1, MMP9, MMP14,PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14, IL10, THBD, or NFKBIA, whereinif IL1B, IL10, or MMP9 is the at least one gene selected in part(c)(ii), then selecting at least a second different gene other thanIL1B, IL10, or MMP9; iii) determining the level of expression of atleast one gene of C13ORF31, C14ORF10, C1ORF51, C1ORF63, CBR4, CB36, CD9,COL6A1, DAB2, GATA2, KIAA0907, LOC100506233, MCM6, MMP1, MS4A4A, MTSS1,PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, or ZCCHC7;iv) determining the level of expression of at least one gene ANXA1,ARRB2, BEAN, BIN1, C1ORF63, CD44, CD9, CFP, COL6A1, CRIP2, EPB41,Fam119a, FOR, FOXO3B, HSD11B1, HSPD1P6, LOC387790, MPEG1, MYB, OLIG1,PLD1, PPP4R2, PRDM1, RBM6, SNX27, S0D2, STATH, TARP, TREM1, TRGC2, UBN2,or ZCCHC7; v) determining the level of expression of at least one geneof ADAMS, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5,ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31, C5ORF13,C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55,CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2,ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, GOS2, HMGB2, HNRPLL,ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL411, INADL, ISG2O, ITGB5,KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA,LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITE, MLF1, MMP1, MMP9, MPEG1,MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4,P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1,RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2,STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6,TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, or VSNL1; vi)determining the level of expression of at least one gene of ACTN4,BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBX045, GAPDHS, HDAC4,H1C2, HNRPD, HSPD1, LOC648342, MYB, NAPS, OXCT2, SERPINB2, SFRS14,SPFH1, STT3B, WDFY1, ZNF250, or ZNF566; vii) determining the level ofexpression of at least one gene of A2M, ABCB1, ABCC3, ABHD2, ACPP,ADAMDEC1, ADFP, ADORA2B, ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2,ANXA2P2, APBB1IP, AQP1, ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9,ATF5, ATP1B1, ATP6V0D2, ATP9A, ATP1OA, AYTL1, BCL2A1, BCL6, C3AR1,C13ORD31, C9ORF88, C9ORF89, C1ORF21, C1ORF22, C10ORF95, C13ORF31,C21ORF7, CARD12, CARD15, CCDC83, CCL5, CCL24, CCND1, CCR1, CD9, CD36,CD52, CD86, CD109, CD180, CD244, CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF,CLEC7A, CNIH3, COL6A1, COL22A1, CRIP2, CSF1R, CSPG4, CTSL, CTSLL3,CX3CR1, CXCR7, CYBB, CYP1B1, DAB2, DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2,DKFZP56400823, DKFZP68601327, EBI2, EMP1, EMR2, ENPP2, EPAS1, EPS8,EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2, FGD2, FGD4, FGL2, FN1, FTH1,GBP2, GBP3, GBP5, GCNT1, GDPD1, GNDL, GNLY, GLIPR1, GLIS3, GPC1, GPR35,H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA, HIVEP1, HMOX1, HSPB7, ICAM1,ID2, ID2B, 19130, 19144, IFNGR1, IGFBP3, IL2RG, IL4I1, IL1ORA, IL27RA,IL7R, IL10, INA, IRF7, ITGB5, ITGB7, KIAA15O5, KIAA1706, KMO, LBH, LFNG,LILRB1, LILRB2, LMNA, LOC51334, LOC201895, LOC284262, LOC51334,LOC643424, LOC643834, LOC643847, LOC644242, LOC645238, LOC650429,LOC650446, LOC652543, LOC653610, LOC653754, LPAAT-THETA, LPXN, MAF,MAFB, MAML2, MAML3, MARCH1, MCOLN3, MDGA1, ME1, MFI1, MFI2, MGC45491,MGLL, MITF, MMP1, MMP2, MMP9, MMP14, MMP19, MTMR11, MTSS1, MTSU1, NGEF,NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E, OAS1, OLR1, P2RY5, P2RY14, PALLD,PAPSS2, PAQR5, PCDHGA1, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6,PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10, PCDHGA11, PCDHGA12, PCDHGB1,PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5,PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4, PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1,POPDC3, PRDM1, PRSS23, PSCDBP, PSD3, PTAFR, PTGS1, PTPRO, PTRF, PTX3,RAB27B, RAB38, RAB7B, RAPH1, RASGRF1, RGL1, RGS13, RHBDF1, RIN2, S100A2,SART2, SERPINE2, SERTAD1, SETBP1, SGIP1, SH3TC1, SKIL, SLA, SLAMF7,SLAMF8, SLC6AS, SLC7A11, SLC12A6, 5LC37A2, SLC41A2, SLC38A6, SLC43A2,SNAI3, ST3GAL5, STATH, STEAP1, SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A,THBD, TLR4, TM7SF4, TMEM39A, TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1,TRIM22, TRPA1, TRPM8, TRPS1, TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF,VSNL1, or ZFP36L1; viii) determining the level of expression of at leastone gene of ABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP8B,C1ORF71, C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27,C20ORF103, C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD,CKAP4, CNTN4, COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2,DZIP1, EBF3, EGR4, FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18,HAL, HNF4G, HSPC049, IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146,KIAA0984, KIAA1026, KIAA1553, KLHL23, LGR4, LOC201164, LOC284454,LOC387763, LOC642083, LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19,NAPSB, NR1D2, PCDH8, PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF,OSBPL1A, OSR2, OXCT2, PGM1, PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A,RASGRP2, RBM3B, RET, RFTN1, SERPINB2, SERPINB10, SLAIN1, SLC1A3,SLC16A1, SLC19A1, SLC27A2, SLC29A1, SLC39A14, SLCO4A1, SNF1LK, SOX12,SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2, TARP, TEAD4, TDRD7, TMEM67, TPD52,TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2, TUBA1, VIT, WDR49, WNT3, WT1, orYES1; ix) determining the level of expression of at least one gene ofAHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, orTIPARP; x) determining the level of expression of at least one gene ofADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5,TIMP3, or TSC22D1; xi) determining the level of expression of at leastone gene of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6, Ifi202b, Ifi203,Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068, LOC100862473, Mx1,Oas11, Phf11d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18, or Zcchc2; xii)determining the level of expression of at least one gene of Ccdc711,D13ERTD608E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech, or Tspan2;xiii) determining the level of expression of at least one gene of Ahrr,AI607873, Atp10a, AW011738, Casp44, Cxc13, Gm9706, Ifi202b, Ifit2,Ifitm6, I118, Lcn2, LOC100044068, Ms4a6d, Mx1, Papd7, Rsad2, Slfn3,Slfn4, Tdrd7, Tiparp, or Zcchc2; xiv) determining the level ofexpression of at least one gene of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3,Fam162a, Gfi1, Gpi1, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm,Tpi1, or Trappc6a; xv) determining the level of expression of at leastone of 1600014C10Rik, 2810474019Rik, 6720475J19Rik, Adam8, Adar, Agrn,Ahrr, AI607873, Amigo2, Ankfy1, Apobec1, Arf4, Asb2, Ascc3, Atp10a,Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chic1, Cmpk2, Csprs,Cxc13, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4, Eif2ak2, Emr1,Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772, Gm14446, Gm15433,Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb, Gpr15, H2-T10, H2-T9,Hck, Helz2, Herc6, Hsh2d, Hspa1b, Ifi202b, Ifi203, Ifi204, Ifi205,Ifi2712a, Ifi35, Ifi44, Ifi441, Ifih1, Ifit1, Ifit2, Ifit3, Ifitm3,I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Klrk1, Lgals3 bp, Lgals9,LOC100041903, LOC100044068, LOC100503923, LOC100505160, LOC100862473,LOC664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitd1, Mlk1, Mmp8, Mnda, Mnda1,Ms4a4c, Ms4a6d, Mx1, Naa20, Nceh1, Ncoa7, Ngp, Nlrc5, Nmral1, Nqo1,Nt5c3, Oas1a, Oas2, Oas3, Oas11, Oas12, Ogfr, Papd7, Parp10, Parp1i,Parp12, Parp14, Phf11d, Pik3ap1, Pla2g7, Plec, Pnpt1, Ppm1k, Pydc4,Pyhin1, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin, Sdc3, Setdb2,Sgcb, Shisa5, Slco3a1, Slfn1, Slfn3, Slfn4, Slfn5, Slfn8, Slfn9,St3gal6, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10, Torlaip2,Tor3a, Trafd1, Trim25, Trim30a, Trim30d, Trim34a, Trim34b, Tspo, Uba7,Ubr4, Usp18, Wnt10a, Xaf1, Xaf1, Zc3hav1, Zcchc2, Zfyve26, Znfx1, orZufsp; xvi) determining the level of expression of at least one gene ofCcdc711, D13ERTD6O8E, Fads2, Gm2a, Ifi2711, Ighm, Klk1, Scd2, Siglech,or Tspan2; xvii) determining the level of expression of at least onegene of CC12, CYBASC3, CYP1B1, FCAR, HBEGF, ID1, IL1B, 1L411, MSC, NQO1,PPP1R15A, PRDM1, SLC7A11, SRXN1, TIPARP, TMEM138, TXNRD1, or VEGF;xviii) determining the level of expression of at least one gene of BCL2,CACNA2D3, C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL,HSPA1A, HSPC049, LOC645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2,SERPINB8, SPFH1, or TDRD7; xix) determining the level of expression ofat least one gene of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP, ADORA2B,ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP, ANKRD57,ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2, ATF5,ATG7, ATP6V0B, ATP6V0C, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3, BCL6,BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35,C13ORF31, C14ORF43, C15ORF39, C17ORF32, C19ORF58, C1ORF122, C1ORF144,C10RF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88,CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD109, CD244, CD300A,CD40, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1A, CHST11, CIDEC, CKB,CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2,CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD,CYLD, CYP1B1, DDB1, DGAT2, DKFZP686O1327, DOC, DOK2, DUSP6, EBI2, ECGF1,ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3, EPB41L3,EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2, FLJ20489,FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1, GNA15,GPR35, GPR6B, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA, HIVEP1,HMOX1, HNRPLL, HPCAL1, ID1, 102, IER5, 1F130, IFNGR1, IFNGR2, IGFBP3,IL1ORA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, IL4I1, IL4R,IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999, KIAA1505,KIAA17O6, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB, LAT, LHX2,LOC113179, LOC338758, LOC440934, LOC54103, LOC644242, LOC648998,LOC650429, LOC650446, LOC651816, LOC653524, LOC653361, LOC653840,LOC653361, LOC653506, LOC653610, LOC653840, LOC653626, LPAAT-THETA, LPL,LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B, MARCKSL1, MBP,MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9, MOBKL2A, MSC,MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1, NFE2L3, NFKB1,NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1, NQO1,NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4, PDLIM4,PECAM1, PEX19, POD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2, PLAU,PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4,PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B,RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2,RIN3, RIT1, RND3, RSNL2, RSPO3, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4,SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3,SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6,SLC37A2, SLC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11,SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1,SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP,TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B,TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3,TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG,ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5,ZFP36L1, ZNF366, ZNF516, or ZNF697; xx) determining the level ofexpression of at least one gene of ABHD14B, ACTN1, ACY1L2, ADA, ADD2,AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL, ARHGEF6,ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8B, BRE,BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41, C16ORF73,C1ORF121, C1ORF63, C1QBP, C1S, C20ORF103, C20ORF112, C20ORF12, C3ORF14,C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2,CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4,CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL5A2, CUGBP2, CXORF21, DAB1,DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152,FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D,GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2,HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, 102,ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF10,LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274,LOC220594, LOC254559, LOC284702, LOC285084, LOC285758, LOC340061,LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456,LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTLE, MICAL1,MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H,MT1M, MTBP, MTHFD1, MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11,NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH,PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3,PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG,SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4,SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1,ST3GAL3, STAR, STREP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1,TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2,VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33,ZBTB44, ZF, ZNF207, ZNF519, ZNF658, or ZNF92; xxi) determining the levelof expression of at least one gene of CCL2, CCL5, CXCL10, IL1RN, orMMP9; xxii) determining the level of expression of at least one gene ofCCL5, CXCL10, or MMP9; xxiii) determining the level of expression of atleast one gene of IL10 or CCL2; xxiv) determining the level ofexpression of at least one gene of IFNg, TNF, CCL3, CXCL8, or IL-10;xxv) determining the level of expression of at least one gene of MMP9,CCL2, CCL5, CXCL1, or IL1B; xxvi) determining the level of expression ofat least one gene of MMP9, CXCL10, CCL2, or CCL5; xxix) determining thelevel of expression of at least one gene of CCL3, MMP9, CCL22, CCL24,CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10, CXCL11,CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, or MIF; or xxx)determining the level of expression of at least one gene of CCL3, MMP9,CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, 1L8, CCL13, CCL5, IL1B, CCL8,IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, MIF, IL16,IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, or CXCL5.
 160. The process ofclaim 159, wherein if the level of expression of ABI2 is upregulatedrelative to the level of expression by the same type of cells in theabsence of the glatiramer acetate related drug substance under the sameconditions then a. i) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of ABCF2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84,CDC6, CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE,IL10, LPHN1, NACA, OLAH, PATZ1, PDK1, POLI, REEP5, RPL5, RPS6KA2,SEC31A, SETBP1, SNRPA1, SYNCRIP, TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13,UBAP2, VAV3, VDAC2, and ZFAND6 is not substantially identical to thelevel of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions; ii)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of BIRC3, CCL24, CCR1,CISH, CSF1R, CX3CR1, CXCL10, HSPD1, ICAM1, IL1B, IFNGR1, IL27, IL2RG,IL7R, IL1RN, MMP1, MMP9, MMP14, PGRMC1, PRDM1, CARD15, CCL2, CCL5, CD14,IL10, THBD, and NFKBIA is substantially identical to the level ofexpression by the same type of cells in the presence of the glatirameracetate drug substance under the same conditions; iii) including thebatch of the glatiramer acetate related drug substance in the productionof the drug product if the level of expression of one or more genesselected from the group consisting of C13ORF31, C14ORF10, C1ORF51,C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2, KIAA0907, LOC100506233,MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7, TAF15, TARP, TIA1, TMF1,TRGC2, TXNDC11, and ZCCHC7 is substantially identical to the level ofexpression by the same type of cells in the presence of the glatirameracetate drug substance under the same conditions; iv) including thebatch of the glatiramer acetate related drug substance in the productionof the drug product it the level of expression of one or more genesselected from the group consisting of ANXA1, ARRB2, BEAN, BIN1, C1ORF63,CD44, CD9, CFP, COL6A1, CRIP2, EPB41, Fam119a, FGR, FOXO3B, HSD11B1,HSPD1P6, LOC387790, MPEG1, MYB, OLIG1, PLD1, PPP4R2, PRDM1, RBM6, SNX27,S0D2, STATH, TARP, TREM1, TRGC2, UBN2, and ZCCHC7 is substantiallyidentical to the level of expression by the same type of cells in thepresence of the glatiramer acetate drug substance under the sameconditions; v) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofADAM9, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2, ARHGAP18, ARHGAP18, ARL6IP5,ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15, C1ORF21, C13ORF31, C5ORF13,C5ORF32, C9ORF13O, CAST, CCL2, CCL5, CD14, CD300A, CD36, CD40, CD55,CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10, CYLD, DAB2, EBI3, EBI2,ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1, CD82, HMGB2, HNRPLL,ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL10RA, IL411, INADL, ISG2O, ITGB5,KIAA1505, KYNU, LACTB, LOC54103, LOC388344, LOC652751, LPAAT-THETA,LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF, MLF1, MMP1, MMP9, MPEG1,MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3, NFE2L3, OSBPL11, P2RX4,P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP, PTX3, RAB27B, RCSD1,RPL13, SGIP1, SLC39A8, SNORD6B, SRPX2, SRA1, SLIC1, SLAMF8, SLIC1, SOD2,STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TGM5, THBD, TNFAIP3, TNFAIP6,TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2, VPS33A, and VSNL1 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions; vi) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3, FAM62A,FBX045, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB, OXCT2,SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions; vii) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of A2M, ABCB1, ABCC3, ABHD2, ACPP, ADAMDEC1, ADFP, ADORA2B,ADORA3, AHNAK, ALCAM, ANKH, ANKRD57, ANXA2, ANXA2P2, APBB1IP, AQP1,ARHGAP18, ARHGAP20, ARHGEF3, ARID5B, ARMC9, ATF5, ATP1B1, ATP6V0D2,ATP9A, ATP10A, AYTL1, BCL2A1, BCL6, C3AR1, C13ORD31, C9ORF88, C9ORF89,C1ORF21, C1ORF21, C10ORF95, C13ORF31, C21ORF7, CARD12, CARD15, CCDC83,CCL5, CCL24, CCND1, CCR1, CD9, CD36, CD52, CD86, CD109, CD180, CD244,CDK5RAP2, CDKN1A, CENTA2, CKB, CKLF, CLEC7A, CNIH3, COL6A1, COL22A1,CRIP2, CSF1R, CSPG4, CTSL, CTSLL3, CX3CR1, CXCR7, CYBB, CYP1B1, DAB2,DAPP1, DDIT4L, DIXDC1, DOCK4, DOK2, DKFZP56400823, DKFZP68601327, E312,EMP1, EMR2, ENPP2, EPAS1, EPS8, EPSTI1, EVL, FABP4, FADS3, FAM26B, FGD2,FGD2, FGD4, FGL2, FN1, FTH1, GBP2, GBP3, GBP5, GCNT1, CD801, GNDL, ONLY,GLIPR1, GLIS3, 0801, GPR35, H2A/R, HAVCR2, HMCN1, HIPK2, HIST2H2AA,HIVEP1, HMOX1, HSPB7, ICAM1, 102, ID2B, IFI30, IFI44, IFNGR1, IGFBP3,IL2RG, IL4I1, IL1ORA, IL27RA, IL7R, IL1O, INA, IRF7, ITGB5, ITGB7,KIAA1505, KIAA1706, KMO, LBH, LFNG, LILRB1, LILRB2, LMNA, LOC51334,LOC201895, LOC284262, LOC51334, LOC643424, LOC643834, LOC643847,LOC644242, LOC645238, LOC650429, LOC650446, LOC652543, LOC653610,LOC653754, LPAAT-THETA, LPXN, MAF, MAFB, MAML2, MAML3, MARCH1, MCOLN3,MDGA1, ME1, MFI1, MFI2, MGC45491, MGLL, MITF, MMP1, MMP2, MMP9, MMP14,MMP19, MTMR11, MTSS1, MTSU1, NGEF, NME7, NPTX1, NRCAM, NRP1, NRP2, NT5E,OAS1, OLR1, P2RY5, P2RY14, PALLD, PAPSS2, PAQR5, PCDHGA1, PCDHGA2,PCDHGA3, PCDHGA4, PCDHGA5, PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGA10,PCDHGA11, PCDHGA12, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4, PCDHGB5,PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PDK4, PDLIM7, PFKFB4, PGA5, PDLIM4,PHLDA1, PLA2G4A, PLEKHA7, PLEKHO1, POPDC3, PRDM1, PRSS23, PSCDBP, PSD3,PTAFR, PTGS1, PTPRO, PTRF, PTX3, RAB27B, RAB38, RAB7B, RAPH1, RASGRF1,RGL1, RGS13, RHBDF1, RIN2, S100A2, SART2, SERPINE2, SERTAD1, SETBP1,SGIP1, SH3TC1, SKIL, SLA, SLAMF7, SLAMF8, SLC6AS, SLC7A11, SLC12A6,5LC37A2, SLC41A2, SLC38A6, SLC43A2, SNAI3, ST3GAL5, STATH, STEAP1,SUCNR1, SYTL1, TBXAS1, TCF4, TFAP2A, THBD, TLR4, TM7SF4, TMEM39A,TMEM158, TNCRNA, TNFSF13B, TNFRSF21, TREM1, TRIM22, TRPA1, TRPM8, TRPS1,TUBB2A, UBXD5, UGCG, UPP1, VASH1, VEGF, VSNL1, and ZFP36L1, isupregulated to the level of expression by the same type of cells in theabsence of the glatiramer acetate related drug substance under the sameconditions; viii) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofABCG1, ADAMTS1, ANKRD41, ANXA3, APCDD1, BCL2, BCL11A, BMP5B, C1ORF71,C1ORF76, C1ORD121, C12ORF24, C16ORF73, C16ORF74, C20ORD27, C20ORF103,C20ORF112, CACNA2D3, CAMTA1, CAV1, CCDC85B, CDCA7L, CEBPD, CKAP4, CNTN4,COL8A2, CSPG5, CXCR4, DCUN1D4, DEPDC6, DMRT2, DUSP2, DZIP1, EBF3, EGR4,FAM117A, FKBP4, FL135848, FLOT2, GFI1, GMDS, GPR18, HAL, HNF4G, HSPC049,IL17D, IRX3, KBTBD11, KCNQ4, KCTD15, KIAA0146, KIAA0984, KIAA1026,KIAA1553, KLHL23, LGR4, LOC201164, LOC284454, LOC387763, LOC642083,LOC648232, MGC2408, MICAL1, MID1IP1, MSRB3, MUC19, NAPSB, NR1D2, PCDH8,PDE4B, PDGFD, PER2, PHF15, PKP2, PLK2, OAF, OSBPL1A, OSR2, OXCT2, PGM1,PMAIP1, PNMA6A, POU4F2, PSAT1, RAB33A, RASGRP2, RBM38, RET, RFTN1,SERPINB2, SERPINB10, SLAIN1, SLC1A3, SLC16A1, SLC19A1, SLC27A2, SLC29A1,SLC39A14, SLCO4A1, SNF1LK, SOX12, SPFH1, SPRY1, STEAP3, SYDE2, SYNPO2,TARP, TEAD4, TDRD7, TMEM67, TPD52, TRGC2, TRGV2, TRGV9, TRIB3, TSPAN2,TUBA1, VIT, WDR49, WNT3, WT1, and YES1, is downregulated to the level ofexpression by the same type of cells in the absence of the glatirameracetate related drug substance under the same conditions; or ix)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of AHRR, CCDC36, CYP1B1,DOC1, EPB41L3, GAS7, GPR68, NPTX1, PDCD6, and TIPARP is substantiallyidentical to the level of expression by the same type of cells in thepresence of the glatiramer acetate drug substance under the sameconditions; x) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofADRB2, COTL1, LOC285758, LOC644137, MALAT1, PRG1, RNF43, SAT1, THAP5,TIMP3, and TSC22D1 is substantially identical to the level of expressionby the same type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xi) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of AW011738, Bst2, Daxx, Gm16340, Hck, Herc6,Ifi202b, Ifi203, Ifi204, Ifi44, Ifi441, Ifit2, Inpp5b, LOC100044068,LOC100862473, Mx1, Oas11, Phf11d, Oyhin1, Sdc3, Setdb2, Tor3a, Usp18,and Zcchc2 is substantially identical to the level of expression by thesame type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xii) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711,Ighm, Klk1, Scd2, Siglech, and Tspan2 is substantially identical to thelevel of expression by the same type of cells in the presence of theglatiramer acetate drug substance under the same conditions; xiii)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of Ahrr, AI607873, Atp10a,AW011738, Casp44, Cxc13, Gm9706, Ifi202b, Ifit2, Ifitm6, I118, Lcn2,LOC100044068, Ms4a6d, Mx1, Papd7, Rsad2, Slfn3, Slfn4, Tdrd7, Tiparp,and Zcchc2 is substantially identical to the level of expression by thesame type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xiv) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of Aldoc, Casp6, Ccdc711, Cox7a1, Egln3, Fam162a,Gfi1, Gpi1, Grhpr, Ifi2711, Ighm, Kcnq5, Klhdc2, Pgk1, Pkm, Tpi1, andTrappc6a is substantially identical to the level of expression by thesame type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xv) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of 1600014C10Rik, 2810474019Rik, 6720475J19Rik,Adam8, Adar, Agrn, Ahrr, A1607873, Amigo2, Ankfy1, Apobec1, Arf4, Asb2,Ascc3, Atp10a, Atp8b4, AW011738, B4galt5, BC147527, Bst2, Casp4, Chic1,Cmpk2, Csprs, Cxc13, Cybb, Daxx, Ddit3, Ddx24, Ddx58, Ddx60, Dpp4,Eif2ak2, Emr1, Epsti1, Evi2a, Fcgr1, Fcgr4, Ftsjd2, Gcnt1, Gm11772,Gm14446, Gm15433, Gm16340, Gm20559, Gm2666, Gm7609, Gm9706, Gpnmb,Gpr15, H2-T10, H2-T9, Hck, Helz2, Herc6, Hsh2d, Hspa1b, Ifi202b, Ifi203,Ifi204, Ifi205, Ifi2712a, Ifi35, Ifi44, Ifi44l, Ifih1, Ifit1, Ifit2,Ifit3, Ifitm3, I118, I17r, Inpp5b, Ins16, Irf7, Isg20, Lgals3 bp,Lgals9, LOC100041903, LOC100044068, LOC100503923, LOC100505160,LOC100862473, LOC664787, Lpar6, Ly6c1, Ly6c2, Mb21d1, Mitd1, Mlk1, Mmp8,Mnda, Mnda1, Ms4a4c, Ms4a6d, Mx1, Naa20, Nceh1, Ncoa7, Ngp, Nlrc5,Nmral1, Nqo1, Nt5c3, Oas1a, Oas2, Oas3, Oas11, Oas12, Ogfr, Papd7,Parp10, Parp11, Parp12, Parp14, Phf11d, Pik3ap1, Pla2g7, Plec, Pnpt1,Ppm1k, Pydc4, Pyhin1, Ramp3, Rnf213, Rnf8, Rsad2, Rtp4, Samd91, Scin,Sdc3, Setdb2, Sgcb, Shisa5, Slco3a1, Slfn1, Slfn3, Slfn4, Slfn5, Slfn8,Slfn9, St3gal6, Tcstv3, Tdrd7, Tiparp, Tmem140, Tmem184b, Tnfsf10,Torlaip2, Tor3a, Trafd1, Trim25, Trim30a, Trim30d, Trim34a, Trim34b,Tspo, Uba7, Ubr4, Usp18, Wnt10a, Xaf1, Xaf1, Zc3hav1, Zcchc2, Zfyve26,Znfx1, and Zufsp is substantially identical to the level of expressionby the same type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xvi) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of Ccdc711, D13ERTD608E, Fads2, Gm2a, Ifi2711,Ighm, Klk1, Scd2, Siglech, and Tspan2 is substantially identical to thelevel of expression by the same type of cells in the presence of theglatiramer acetate drug substance under the same conditions; xvii)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of CC12, CYBASC3, CYP1B1,FCAR, HBEGF, ID1, IL1B, IL411, MSC, N(201, PPP1R15A, PRDM1, SLC7A11,SRXN1, TIPARP, TMEM138, TXNRD1, and VEGF is substantially identical tothe level of expression by the same type of cells in the presence of theglatiramer acetate drug substance under the same conditions; xviii)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of BCL2, CACNA2D3,C13ORF18, C20ORF103, C5ORF13, CDCA7, DEPDC6, GATM, HAL, HSPA1A, HSPC049,LOC645919, LRMP, OAF, POU4F2, RASGRP2, RET, SERPINB2, SERPINB8, SPFH1,and TDRD7 is substantially identical to the level of expression by thesame type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xix) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of ABCC1, ABHD12, ABHD5, ACPP, ACSL1, ADFP,ADORA2B, ADORA3, AHRR, AKNA, AKR1C1, AKR1C2, AKR1C3, ALAS1, ALOX5AP,ANKRD57, ANXA2, APBB1IP, APRIN, ARHGAP20, ARHGEF3, ARRB2, ARRDC4, ASB2,ATF5, ATG7, ATP6V0B, ATP6V0C, ATP9A, ATP9B, AXL, AYTL1, BCL2A1, BCL3,BCL6, BHLHB2, BTG1, BTG2, BTG3, C10ORF22, C10ORF54, C10ORF56, C12ORF35,C13ORF31, C14ORF43, C15ORF39, C17ORF32, C19ORF58, C1ORF122, C1ORF144,C1ORF162, C1ORF21, C1ORF38, C3AR1, C5ORF20, C6ORF166, C9ORF16, C9ORF88,CALN1, CARD15, CCL2, CCL5, CCND3, CCNL1, CCR1, CD1O9, CD244, CD300A,C040, CD44, CD83, CD9, CDCA4, CDK5RAP2, CDKN1A, CHST11, CIDEC, CKB,CLEC5A, CLEC7A, CMTM3, CPEB2, CPEB4, CSF1R, CSGLCA-T, CSGLCA-T, CSPG2,CSPG2, CTSB, CTSH, CUTL1, CXCL1, CXCL2, CXXC5, CYBASC3, CYBB, CYLD,CYLD, CYP1B1, DDB1, DGAT2, DKFZP68601327, DOC1, DOK2, DUSP6, EBI2,ECGF1, ECOP, EFHD2, EIF1, ELL2, ELOVL1, EMP2, EMR2, EPAS1, EPB41L3,EPB41L3, EXT1, F3, FADS3, FAM100B, FCAMR, FCAR, FGD3, FGD4, FGL2,FLJ20489, FLJ20701, FLJ90013, FLRT2, FPRL1, FTH1, FUCA1, GAS7, GCNT1,GNA15, GPR35, GPR68, GSR, GSR, H2A, HBEGF, HERPUD1, HIPK2, HIST2H2AA,HIVEP1, HMOX1, HNRPLL, HPCAL1, ID1, 102, IER5, IFI30, IFNGR1, IFNGR2,IGFBP3, IL10RA, IL1B, IL1R1, IL1RN, IL1RN, IL21R, IL27RA, IL27RA, 1L411,IL4R, IRF5, ITGB7, JDP2, JUN, JUNB, JUND, KCNN4, KIAA0247, KIAA0999,KIAA1505, KIAA17O6, KIAA1913, KITLG, KLF13, KLF4, KLF6, KLHL18, LACTB,LAT, LHX2, LOC113179, LOC338758, LOC440934, LOC54103, LOC644242,LOC648998, LOC650429, LOC650446, LOC651816, LOC653524, LOC653361,LOC653840, LOC653361, LOC653506, LOC653610, LOC653840, LOC653626,LPAAT-THETA, LPL, LPXN, LRG1, LRP10, MAFB, MAFF, MALT1, MAML2, MAP1LC3B,MARCKSL1, MBP, MCL1, ME1, METRNL, MGAT4A, MGC13379, MGLL, MMP2, MMP9,MOBKL2A, MSC, MST150, MTF1, MTUS1, MYH10, NAB1, NCF1, NCF2, NCF4, NEU1,NFE2L3, NFKB2, NFKBIA, NFKBIE, NFXL1, NINJ1, NOTCH1, NOTCH2NL, NPTX1,NQO1, NRP1, NRP2, NT5E, NUAK1, P2RY5, P2RY6, PACSIN2, PDCD6, PDK4,PDLIM4, PECAM1, PEX19, PGD, PHLDA1, PHLDA2, PIK3R5, PIR, PITPNA, PKM2,PLAU, PLAUR, PLEKHO1, PNKD, POPDC3, PPIF, PPP1R15A, PRDM1, PRKCA, PSCD4,PSCDBP, PSMD1, PTAFR, PTGS1, PTPN14, PTPRE, PTX3, QPRT, RAB13, RAB27B,RAB38, RAB6IP1, RAI17, RAP2B, RAPGEF1, RCN1, RELB, RGL1, RGS1, RGS2,RIN3, RIT1, RND3, RSNL2, RSPO3, RUNX3, SAMSN1, SAP30, SASH1, SAT1, SDC4,SEMA4C, SERPINE2, SERTAD1, SFRS7, SGK, SH3GL1, SH3TC1, SLAMF8, SLC15A3,SLC16A3, SLC20A1, SLC23A2, SLC25A14, SLC25A19, SLC25A20, SLC2A1, SLC2A6,SLC37A2, SLC39A8, SLC43A2, SLC45A3, SLC4A2, SLC4A5, SLC6A6, SLC7A11,SLC7A11, SLIC1, SMOX, SNAI3, SOD2, SPRY2, SPSB1, SQRDL, SQSTM1, SRXN1,SSH1, ST3GAL5, STAT1, STK40, TFAP2A, TFDP1, TFEB, TGIF, THBD, TIPARP,TMEM138, TMTC1, TNFAIP3, TNFAIP6, TNFAIP8L1, TNFRSF10D, TNFRSF1B,TNFRSF21, TNFSF13B, TNFSF7, TP53BP2, TRAF3, TRAF3IP2, TRIB1, TRIB3,TRIM16, TRIM16L, TRPA1, TRPS1, TRPS1, TSHZ3, TTLL4, TXNRD1, UBE2S, UGCG,ULBP2, UPP1, URP2, VASH1, VEGF, VSNL1, YRDC, ZBTB24, ZCCHC10, ZFAND5,ZFP36L1, ZNF366, ZNF516, and ZNF697 is substantially identical to thelevel of expression by the same type of cells in the presence of theglatiramer acetate drug substance under the same conditions; xx)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of ABHD14B, ACTN1, ACY1L2,ADA, ADD2, AFF1, AIG1, AK2, AKAP1, ALS2CR13, ANKRD45, ANKRD55, APPL,ARHGEF6, ATG16L2, ATP8B3, ATP8B4, ATPBD1C, B3GNT7, BCL11A, BCL2, BMP8F,BRE, BSPRY, BTBD14A, C13ORF18, C13ORF18, C14ORF106, C15ORF41, C16ORF73,C1ORF121, C1ORF63, C1QBP, CIS, C20ORF103, C20ORF112, C20ORF12, C3ORF14,C5ORF13, C6ORF147, C7ORF24, C9ORF103, CABC1, CACNA2D3, CACYBP, CALCOCO2,CAMSAP1L1, CAMSAP1L1, CAT, CAV1, CDCA7, CERKL, CHST12, CHST5, CITED4,CLINT1, CLSTN2, CLTCL1, CNTN4, COL4A1, COL8A2, CUGBP2, CXORF21, DAB1,DENND4A, DEPDC6, DHRS9, DMRT2, DUT, EIF4A2, ESD, FLJ12078, FLJ20152,FLJ23861, FLJ36166, FOXP1, GATM, GGA2, GOLGA1, GOLGA8C, GOLGA8D,GOLGA8E, GOLGA8F, GOLGA8G, GPD1L, GPR18, HADH, HAL, HDAC9, HGF, HIG2,HISPPD1, HNRPA3, HNRPH3, HOXB3, HSPA1A, HSPA4L, HSPB1, HSPC049, 102,ID2B, IDH1, IDH1, IHPK2, IRX3, ITGA4, KBTBD11, KCNN2, KIAA0960, KLF1O,LARS, LGR4, LIMA1, LIX1L, LOC129285, LOC148203, LOC197322, LOC203274,LOC220594, LOC254559, LOC284702, LOC285084, LOC285758, LOC340061,LOC340061, LOC388189, LOC474170, LOC643458, LOC645919, LOC646456,LOC90835 LONRF1, LRMP, LYST, MACF1, MDH1, METTL7B, METTLE, MICAL1,MLSTD1, MNDA, MRPL24, MS4A3, MS4A4A, MS4A6A, MS4A7, MSRB3, MT1E, MT1H,MT1M, MTBP, MTHFD1, MTL5, MTR, MUC19, MUM1, MYADM, NAPSB, NAPSB, NAT11,NOC2L, NPAL3, OAF, OCRL, OMA1, OSBPL1A, OXCT2, PDCD4, PHACTR3, PHYH,PIGM, PIWIL4, PNMA6A, POU4F2, PRKAB2, PRLR, PSAT1, PSAT1, PTGER3,PTPLAD2, RABGAP1L, RAD17, RASGRP2, RBKS, RET, RNASEH2B, RNASET2, SELPLG,SERPINB10, SERPINB2, SERPINB8, SERPINI2, SKAP2, SLAIN1, SLC16A4,SLC22A15, SLC22A16, SLC40A1, SMARCA2, SNAPC3, SNX10, SPFH1, SPTBN1,ST3GAL3, STAR, STRBP, SYNPO2, TADA1L, TCFL5, TDRD7, THTPA, TIFA, TLE1,TMEM14A TOP2B, TPD52, TPM1, TRAF3IP3, TSPAN2, TTC9C, UBE2B, UBP1, UHRF2,VLDLR, VPS35, WASF1, WDFY1, WDR49, WDR68, WHDC1L1, WHDC1L2, ZBTB33,ZBTB44, ZF, ZNF207, ZNF519, ZNF658, and ZNF92 is substantially identicalto the level of expression by the same type of cells in the presence ofthe glatiramer acetate drug substance under the same conditions; xxi)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of CCL2, CCL5, CXCL10,IL1RN, and MMP9 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xxii) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of CCL5, CXCL10, and MMP9 is substantiallyidentical to the level of expression by the same type of cells in thepresence of the glatiramer acetate drug substance under the sameconditions; xxiii) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofIL10 and CCL2 is substantially identical to the level of expression bythe same type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; xxiv) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of IFNg, TNF, CCL3, CXCL8, and IL-10 issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions; xxv) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of MMP9, CCL2, CCL5, CXCL1, and IL1B is substantiallyidentical to the level of expression by the same type of cells in thepresence of the glatiramer acetate drug substance under the sameconditions; xxvi) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofMMP9, level of expression by the same type of cells in the presence ofthe glatiramer acetate drug substance under the same conditions; xxix)including the batch of the glatiramer acetate related drug substance inthe production of the drug product if the level of expression of one ormore genes selected from the group consisting of CCL3, MMP9, CCL22,CCL24, CX3CL1, CCL20, CCL2, TNF, IL8, CCL13, CCL5, IL1B, CCL8, IL10,CXCL11, CXCL13, CXCL10, CCL7, CCL1, CXCL1, IFNg, CCL26, and MIF issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions; or xxx) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of CCL3, MMP9, CCL22, CCL24, CX3CL1, CCL20, CCL2, TNF, IL5,CCL13, CCL5, IL1B, CCL8, IL10, CXCL11, CXCL13, CXCL10, CCL7, CCL1,CXCL1, IFNg, CCL26, MIF, 1L16, IL6, CCL25, IL2, CCL19, CXCL2, CXCL9, andCXCL5 is substantially identical to the level of expression by the sametype of cells in the presence of the glatiramer acetate drug substanceunder the same conditions; b. i) including the batch of the glatirameracetate related drug substance in the production of the drug product ifthe level of expression of one or more genes selected from the groupconsisting of ARPC4, CD84, CLU, HFE, and IL10 is upregulated relative tothe level of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions; orii) including the batch of the glatiramer acetate related drug substancein the production of the drug product if the level of expression of oneor more genes selected from the group consisting of ABCF2, ACP6, AFG3L2,CHAF1A, COX11, LPHN1, NACA, OLAH, POLI, SEC31A, SNRPA1, SYNCRIP, TNFSF9,TOMM4O, TSHZ1, TSPAN13, UBAP2, VDAC2, and TSHZ1 is downregulatedrelative to the level of expression by the some type of cells in theabsence of the glatiramer acetate related drug substance under the sameconditions; c. i) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofCCL2, CCL5, MMP1, MMP9, CXCL10, CARD15, CD14, ICAM1, BIRC3, THBD,NFKBIA, IL10, PRDM1 is substantially identical to the level ofexpression by the same type of cells in the presence of glatirameracetate drug substance under the same conditions; ii) including thebatch of the glatiramer acetate related drug substance in the productionof the drug product if the level of expression of one or more genesselected from the group consisting of CISH and HSPD1 is substantiallyidentical to the level of expression by the same type of cells in thepresence of glatiramer acetate drug substance under the same conditions;iii) including the batch of the glatiramer acetate related drugsubstance in the production of the drug product if the level ofexpression of one or more genes selected from the group consisting ofCC124, CCR1, CSF1R, CX3CR1, IL27, IFNGR1, IL2RG, and IL7R is notsubstantially identical to the level of expression by the same type ofcells in the absence of the glatiramer acetate drug related substanceunder the same conditions; iv) including the batch of the glatirameracetate related drug substance in the production of the drug product ifthe level of expression of PGRMC1 is upregulated or substantiallyidentical to the level of expression by the same type of cells in theabsence of the glatiramer acetate related drug substance under the sameconditions; v) including the batch of the glatiramer acetate relateddrug substance in the production of the drug product if the level ofexpression of MMP14 is substantially identical to the level ofexpression by the same type of cells in the presence of glatirameracetate drug substance under the same conditions; vi) including thebatch of the glatiramer acetate related drug substance in the productionof the drug product if the level of expression of IL1RN is upregulatedto the level of expression by the same type of cells in the absence ofthe glatiramer acetate related drug substance under the same conditions;or vii) including the batch of the glatiramer acetate related drugsubstance in the production of the drug product if the level ofexpression of IL1B is substantially identical to the level of expressionby the same type of cells in the presence of glatiramer acetate drugsubstance under the same conditions; d. i) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of ADAMS, ADAMDEC1, AKR1C2, ANXA2, ANXA2P2,ARHGAP18, ARHGAP18, ARL6IP5, ARL6IP5, ATP2C1, BID, BIRC3, BTG1, CARD15,C1ORF21, C13ORF31, C5ORF13, C5ORF32, C9ORF130, CAST, CCL2, CCL5, CD14,CD300A, CD36, CD40, CD55, CD9, CENTA2, CHST11, COL6A1, CRYBB2, CXCL10,CYLD, DAB2, EBI3, EBI2, ECOP, EGF, FABP4, FXYD2, GHRL, GIMAP8, GLIPR1,G0S2, HMGB2, HNRPLL, ICAM1, ICAM2, IFIH1, IFNGR1, IL10, IL1ORA, IL411,INADL, ISG20, ITGB5, KIAA1505, KYNU, LACTB, LOC54103, LOC388344,LOC652751, LPAAT-THETA, LPXN, MAFB, MALT1, MFI2, MGC5618, MGLL, MITF,MLF1, MMP1, MMP9, MPEG1, MTSS1, MXD1, NT5E, NFKBIE, NFKBIA, NFE2L3,NFE2L3, OSBPL11, P2RX4, P2RY5, PLEKHO1, POPDC3, PLAUR, PRDM1, PSCDBP,PTX3, RAB27B, RCSD1, RPL13, SGIP1, SLC39A8, SNORD68, SRPX2, SRA1, SLIC1,SLAMF8, SLIC1, SOD2, STATH, STEAP1, SYNJ2, SYNJ2, TATDN3, TOMS, THBD,TNFAIP3, TNFAIP6, TNFRSF9, TNFSF13B, TPSAB1, TPSB2, TREM1, TXNL2,VPS33A, and VSNL1, is substantially identical to the level of expressionby the same type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; or) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of ACTN4, BTBD14A, C14ORF10, CISH, CLK1, CRLF3,FAM62A, FBX045, GAPDHS, HDAC4, HIC2, HNRPD, HSPD1, LOC648342, MYB, NAPB,OXCT2, SERPINB2, SFRS14, SPFH1, STT3B, WDFY1, ZNF250, and ZNF566, issubstantially identical to the level of expression by the same type ofcells in the presence of the glatiramer acetate drug substance under thesame conditions; or e. i) including the batch of the glatiramer acetaterelated drug substance in the production of the drug product if thelevel of expression of one or more genes selected from the groupconsisting of AHRR, CCDC36, CYP1B1, DOC1, EPB41L3, GAS7, GPR68, NPTX1,PDCD6, and TIPARP is substantially identical to the level of expressionby the same type of cells in the presence of the glatiramer acetate drugsubstance under the same conditions; or ii) including the batch of theglatiramer acetate related drug substance in the production of the drugproduct if the level of expression of one or more genes selected fromthe group consisting of ADRB2, COTL1, LOC285758, LOC644137, MALAT1,PRG1, RNF43, SAT1, THAP5, TIMP3, and TSC22D1 is substantially identicalto the level of expression by the same type of cells in the presence ofthe glatiramer acetate drug substance under the same conditions. 161.The process of claim 101, wherein step (c) further comprises determiningthe level of expression of at least one gene of ACP6, AQP1, DAPP1, GBP2,GBP3, NME7, PLA2G4A, SKIL or TMEM158.
 162. The process of claim 161,wherein if the level of expression of ABI2 is upregulated relative tothe level of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions, andif the level of expression of at least one gene of AQP1, DAPP1, GBP2,GBP3, NME7, PLA2G4A, SKIL or TMEM158 is upregulated relative to thelevel of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions,then including the batch of the glatiramer acetate related drugsubstance in the production of the drug product.
 163. The process ofclaim 101, wherein step (c) further comprises determining the level ofexpression of at least one gene of ABCG1, ACP6, CAMTA1, CCDC85B, CXCR4,EPB41, FAM117A, FLOT2, GYPC, LPHN1, NR1D2, PATZ1 or TSHZ1.
 164. Theprocess of claim 163, wherein if the level of expression of ABI2 isupregulated relative to the level of expression by the same type ofcells in the absence of the glatiramer acetate related drug substanceunder the same conditions, and a. if the level of expression of at leastone gene of ABCG1, ACP6, CAMTA1, CCDC85B, CXCR4, FAM117A, FLOT2, LPHN1or NR1D2 is downregulated relative to the level of expression by thesame type of cells in the absence of the glatiramer acetate related drugsubstance under the same conditions; b. if the level of expression of atleast one gene of GYPC or PATZ1 is not substantially identical to thelevel of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions; orc. if the level of expression of EPB41 is substantially identical to thelevel of expression by the same type of cells in the presence of theglatiramer acetate drug substance under the same conditions, thenincluding the batch of the glatiramer acetate related drug substance inthe production of the drug product.
 165. The process of claim 101,wherein step (c) further comprises determining the level of expressionof at least one gene of ACP6 or LPHN1.
 166. The process of claim 165,wherein if the level of expression of ABI2 is upregulated relative tothe level of expression by the same type of cells in the absence of theglatiramer acetate related drug substance under the same conditions, andif the level of expression of at least one gene of ACP6 or LPHN1 isdownregulated relative to the level of expression by the same type ofcells in the absence of the glatiramer acetate related drug substanceunder the same conditions, then including the batch of the glatirameracetate related drug substance in the production of the drug product.167. The process of claim 159, wherein step (c) further comprises i)determining the level of expression of at least one gene of ABCF2,AFG3L2, ALMS1, ARPC4, CALMS, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11,DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, NACA, OLAH, PATZ1,PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP,TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, or ZFAND6; ii)determining the level of expression of at least one gene of C13ORF31,C14ORF10, C1ORF51, C1ORF63, CBR4, CB36, CD9, COL6A1, DAB2, GATA2,KIAA0907, LOC100506233, MCM6, MMP1, MS4A4A, MTSS1, PCMTD1, STK4, STX7,TAF15, TARP, TIA1, TMF1, TRGC2, TXNDC11, or ZCCHC7; or iii) determiningthe level of expression of at least one gene of ACTN4, BTBD14A,C14ORF10, CISH, CLK1, CRLF3, FAM62A, FBX045, GAPDHS, HDAC4, HIC2, HNRPD,HSPD1, LOC648342, MYB, NAPB, OXCT2, SERPINB2, SFRS14, SPFH1, STT3B,WDFY1, ZNF250, or ZNF566, wherein all genes ABCF2, ABI2, ACP6, AFG3L2,ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6, CHAF1A, CLU, COX11, DLGAP1,DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, IL10, LPHN1, NACA, OLAH, PATZ1,PDK1, POLI, REEP5, RPL5, RPS6KA2, SEC31A, SETBP1, SNRPA1, SYNCRIP,TNFSF9, TOMM40, TPM1, TSHZ1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6,are selected for determining the level of expression, wherein all genesABCF2, ABI2, ACP6, AFG3L2, ALMS1, ARPC4, CALM3, CCDC64, CD84, CDC6,CHAF1A, CLU, COX11, DLGAP1, DTX4, FAM49B, FHL1, FNTB, GYPC, HFE, LPHN1,OLAH, PATZ1, PDK1, POLI, REEFS, RPS6KA2, SEC31A, SETBP1, SNRPA1,SYNCRIP, TNFSF9, TOMM40, TPM1, TSPAN13, UBAP2, VAV3, VDAC2, and ZFAND6,are selected for determining the level of expression, and wherein instep (c)(i), if IL10 is the at least one gene selected in part(c)(1),then selecting at least a second different gene from other than IL10, orwherein in step (c) (ii), if CARD15, CCL2, CCL5, CD14, IL10, THBD, orNFKBIA is the at least one of gene is selected in part (c)(ii), thenselecting at least a second different gene from (c)(i) or c(ii) otherthan CARD15, CCL2, CCL5, CD14, IL10, THBD, or NFKBIA, and wherein if twoor more genes are selected in step (c), then the second or additionalgene selected is different from the other selected gene or genes. 168.The process of claim 159 comprising, the step of (c)(vii) or (c)(viii),wherein the level of expression is determined for all genes identifiedin Table 5 or Table 12 to be involved in one or more than one pathway,at least one pathway, two or more pathways, three or more pathways, fouror more pathways, five or more pathways, six pathways; wherein the levelof expression is determined for at least one gene which is involved inonly one pathway set forth in Table 5 or Table 12; or wherein the levelof expression is determined for at least two genes, at least threegenes, at least tour genes, at least five genes, or at least six genesidentified in Table 5 or Table 12 to be involved in the same pathway, orthe step of (c) (v) or (C) (vi), wherein the level of expression isdetermined for all genes identified in Table 6 to be involved in one ormore than one pathway, at least one pathway, two or more pathways, threeor more pathways, four or more pathways, five or more pathways, six ormore pathways, or at least one gene which is involved in only onepathway set forth in Table 6; or wherein the level of expression isdetermined for at least two genes, at least three genes, at least fourgenes, at least five genes, or at least six genes identified in Table 6to be involved in the same pathway.